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Review

MicroRNA in Lung Cancer Metastasis

by
Shang-Gin Wu
1,2,
Tzu-Hua Chang
1,
Yi-Nan Liu
1 and
Jin-Yuan Shih
1,3,*
1
Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei 10002, Taiwan
2
Department of Internal Medicine, National Taiwan University Cancer Center, National Taiwan University, Taipei 10672, Taiwan
3
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(2), 265; https://doi.org/10.3390/cancers11020265
Submission received: 31 January 2019 / Revised: 17 February 2019 / Accepted: 18 February 2019 / Published: 23 February 2019
(This article belongs to the Special Issue MicroRNA-Associated Cancer Metastasis)
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Abstract

:
Tumor metastasis is a hallmark of cancer, with distant metastasis frequently developing in lung cancer, even at initial diagnosis, resulting in poor prognosis and high mortality. However, available biomarkers cannot reliably predict cancer spreading sites. The metastatic cascade involves highly complicated processes including invasion, migration, angiogenesis, and epithelial-to-mesenchymal transition that are tightly controlled by various genetic expression modalities along with interaction between cancer cells and the extracellular matrix. In particular, microRNAs (miRNAs), a group of small non-coding RNAs, can influence the transcriptional and post-transcriptional processes, with dysregulation of miRNA expression contributing to the regulation of cancer metastasis. Nevertheless, although miRNA-targeted therapy is widely studied in vitro and in vivo, this strategy currently affords limited feasibility and a few miRNA-targeted therapies for lung cancer have entered into clinical trials to date. Advances in understanding the molecular mechanism of metastasis will thus provide additional potential targets for lung cancer treatment. This review discusses the current research related to the role of miRNAs in lung cancer invasion and metastasis, with a particular focus on the different metastatic lesions and potential miRNA-targeted treatments for lung cancer with the expectation that further exploration of miRNA-targeted therapy may establish a new spectrum of lung cancer treatments.

1. Introduction

Lung cancer constitutes the leading cause of cancer death worldwide [1], with most patients presenting advanced disease stage at initial diagnosis. Although early screening by computed tomography (CT) reduces the associated mortality [2], tumor invasion and migration-mediated disease progression represents the leading cause of cancer-related death despite standard treatment.
Numerous studies regarding tumor invasion and migration depict the interaction between tumor cells and adjacent tissues or microenvironments, reporting different mechanisms and various signal pathways related to tumor spreading. Specifically, the critical role of the epithelial-to-mesenchymal transition (EMT) in cancer invasion, migration, and metastasis provides a clue to prevent cancer spread and identify possible therapeutic targets [3].
MicroRNAs (miRNAs), a group of small non-protein-coding RNAs (20–25 nucleotides), suppress gene expression primarily through direct interaction with the 3′-untranslated region (3′UTR) of corresponding target messenger RNAs (mRNAs) [4]. Target mRNA fate depends on the seed match architecture between the miRNA binding and mRNA seeding sequences. mRNA degradation is induced upon perfect miRNA complementary with the seeding sequence, whereas imperfect or partial complementarities effect protein translational suppression [4]. The imperfect matching and relatively short paired seeding sequences allow miRNAs to regulate various target mRNAs. Identifying different miRNA expression patterns thus supports tissue-specific miRNA classification, and disease status and outcome prediction [5,6]. Aberrantly expressed miRNAs in different malignancies function as tumor suppressors or oncomirs [7,8], regulating cancer biology by controlling target mRNA expression to facilitate tumor growth, invasion, angiogenesis, and immune evasion [9,10]. Here, we review current findings regarding the role of miRNAs in lung cancer invasion and metastasis, focusing on the different metastatic lesions and potential miRNA-targeted treatments.

2. EMT: The Key Mechanism of Lung Cancer Metastasis

Distant spreading of the primary tumor represents the major cause of cancer-related deaths in non-small cell lung cancer (NSCLC), especially metastasis to the brain [11,12]. Metastasis is a complex process by which cancer cells spread from a localized lesion to systemic disease. The “metastatic cascade” includes tumor cells surmounting physical boundaries, basement membrane and surrounding tissue invasion, entry into the blood/lymphatic stream (migration and intravasation), extravasation at the secondary sites, and proliferation [13,14]. EMT encompasses the various molecular factors, phenotype changes, and genetic alterations in the multistep dissemination process [15,16]. Conversely, cell spread and proliferation as metastatic lesions requires a mesenchymal-to-epithelial transition [17] (Figure 1).
In epithelial-to-mesenchymal transition (EMT), uncontrolled epithelial cells first reduce dependence on their normal tissue microenvironment and proliferate [18]. Polarized epithelial cells lose epithelial cell junctional proteins, such as E-cadherin, claudins, and zona-occludens 1 (ZO-1), gaining mesenchymal markers including N-cadherin, vimentin, and fibronectin, with cytoskeletal reorganization. EMT, which engages different molecular process, transcription factor (TF) activation, and alternative miRNA expression [16], occurs in various physiological or pathological processes and is categorized according to biological and functional consequences: fertilized oocyte implantation and embryonic gastrulation (Type 1); inflammation and fibrosis (Type 2); and cancer cell invasion and metastasis (Type 3) [19]. In cancers, epithelial malignant cells acquire mesenchymal characteristics to promote migratory capacity, invasiveness, resistance against apoptosis, and extracellular matrix (ECM) component production [16,20].
Numerous genetic and epigenetic alternations are associated with type 3 EMT, which is driven by intrinsic oncogenic activation (e.g., Kirsten rat sarcoma viral oncogene homolog (KRAS), human epidermal growth factor receptor 2 (Her2), hepatocyte growth factor receptor (MET), and epidermal growth factor receptor (EGFR)) [21,22,23,24,25,26] or external microenvironmental stimuli (myofibroblasts, cancer-associated fibroblasts, infiltrating immune cells, ECM, growth factors (transforming growth factor-β (TGF-β), EGF, hepatocyte growth factor (HGF), and platelet-derived growth factor (PDGF)), and cytokines (tumor necrosis-α (TNF-α) and interleukin-6 (IL-6)) [3,16]. Cell surface proteins, such as αV integrins, also induce EMT by activating TGF-β1 [27]. Such microenvironmental stromal cell-produced factors activate diverse signaling pathways including TGF-β/bone morphogenic protein (BMP), wingless-type murine mammary tumor virus (MMTV) integration site family (WNT)/β-catenin, Sonic hedgehog (SHH), Notch, and phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) [16], along with EMT-inducing TFs, such as Snail gene family (Snail and Slug), zinc finger E-box binding homeobox 1 (ZEB1), ZEB2 (Smad interacting protein 1 (SIP1)/ZFXH1b), lymphoid enhancer binding factor (LEF-1), Twist, and forkhead Box C2 (FOXC2) [3,16,28,29,30]. EMT initiation leads associated intracellular signaling network activation, involving signal-transducing proteins, PI3K, AKT, Ras, mitogen-activated protein kinase (MAPK), extracellular-signal-regulated kinase (ERK), Smads, Ras Homolog Family Member B (RhoB), c-Fos, β-catenin, and lymphoid enhancer binding factor (LEF).

3. MicroRNAs Regulate EMT in Lung Cancer

Accumulating evidence suggests that miRNAs comprise key regulators to control EMT signaling pathways and TFs. Because some miRNAs directly target EMT-TF, miRNAs and EMT-TF form tightly interconnected negative feedback loops that regulate the expression of TF, epithelial cell plasticity, and cell invasion/migration. Therefore, alterations in miRNAs expression have impacts on EMT program and metastasis cascade in cancer [31]. Although it is still poorly known about the regulation of miRNAs expression linked to EMT, more and more signal pathways and mechanisms are explored and clarified. Various miRNAs also regulate EMT in NSCLC (Figure 1 and Table 1).

3.1. SNAI Family TF-Related miRNAs

The Snail gene family encodes three TFs: SNAI1 (also designated as SNAIL), SNAI2 (SLUG), and SNAI3 (SMUC). Their activation down-regulates epithelial gene expression including E-cadherin, and up-regulates that of mesenchymal genes; e.g., N-cadherin, β-catenin, and fibronectin [32]. Various miRNAs regulate EMT by directly targeting the Snail family.
The p53/miR-34 axis regulates Snail expression in different cancer cell lines including lung cancer. p53 knockdown induces SNAIL protein expression by down-regulating miR-34 expression [33]. MiR-126 regulates lung cancer cell invasion and migration in vitro and in vivo, suppressing EMT by directly targeting PI3K/AKT/Snail signaling [34]. MiR-346, which is up-regulated in NSCLC compared with adjacent normal lung tissues, acts as an oncogenic miRNA to promote cell proliferation, metastasis, and decrease cell apoptosis by regulating the xeroderma pigmentosum, complementation group C (XPC)/ERK/SNAIL/E-cadherin pathway [35]. MiR-22 and miR-30a, which are down-regulated in NSCLC, directly target Snail to regulate EMT [36,37,38]. Their overexpression in lung cancer cell lines suppresses invasion and migration and attenuates EMT, including increased E-cadherin expression and decreased N-cadherin level. Finally, miR-381 targets both Snail and Twist [39].
MiR-137 promotes lung cancer invasion and metastasis by suppressing transcription factor AP-2 gamma (TFAP2C). Patients harboring lung adenocarcinoma with low-level Slug and miR-137 albeit high-level TFAP2C expression exhibit significantly longer overall survival (OS) [53]. MiR-124 regulates NSCLC cell invasion by translationally suppressing Slug and modulates resistance to gefitinib, an EGFR tyrosine kinase inhibitor (TKI) [46,47]. As a tumor suppressor; miR-218 expression level inversely correlates with advanced stage and lymph node metastasis. MiR-218 overexpression in lung cancer cell lines induces higher E-cadherin and lower vimentin expression levels. It inhibits EMT, tumor cell migration, and invasion by directly targeting Slug [59].
MiR-1 also directly targets Slug to regulate EMT. MiR-1 overexpression in A549 lung cancer cells causes significant morphological change from mesenchymal to epithelial phenotype with increased E-cadherin, attenuating invasion and migration [40]. Vascular endothelial growth factor-A (VEGF-A) induces sex determining region Y-box 2 (Sox2) to drive stem cell expansion by down-regulating miR-452, which directly targets the SLUG 3′UTR to suppress metastasis, causing Slug up-regulation [64].

3.2. ZEB1/ZEB2 TF-Related miRNAs

ZEB1/ZEB2, well-characterized EMT TFs, mediate cell plasticity, metastasis, and treatment resistance in different cancers [107,108,109]. ZEB1/ZEB2 repress E-cadherin transcription by binding to E-box sites in the ZEB1/ZEB2 promoters via their zinc finger motifs. ZEB1 overexpression in normal immortal human bronchial epithelial cells directly suppresses epithelial splicing regulatory protein 1 expression, thereby up-regulating mesenchymal CD44 splice variant expression to elicit a more invasive phenotype [110].
The widely studied miR-200 family is crucial in cancer initiation and metastasis [111]. Their promoter regions are bound by the TFs ZEB1, ZEB2, p53, specificity protein-1 (Sp1), and Wnt inhibitory factor 1 [112]. Upon promoter binding, ZEB1 and ZEB2 inhibit miR-200 family transcription, whereas p53 and Sp1 activate miR-200b/200a/429 and miR-200c/141 cluster transcription, respectively [81,112,113,114]. The highly invasive lung cancer cells H1299, A549, and SPC-A-1sci are characterized by lower miR-200c expression levels. MiR-200c inhibits invasion and metastasis by directly targeting ubiquitin specific peptidase 25 (USP25) [115]. Up-regulated miR-200c in A549 cells alters cell morphology and causes ZEB1 loss with increase of its regulatory target, E-cadherin [116]. MiR-200c dysregulation is associated with tumor progression, EMT, and drug resistance [117,118]. Notably, the miR-200 family also directly suppresses ZEB1 in a negative feedback loop; this reciprocal repression stabilizes EMT and promotes invasion [81]. MiR-200/ZEB1 axis-related EMT is also associated with antitumor immunity suppression, with the EMT regulatory axis controlling PD-L1 expression on tumor cells. PD-L1 inhibitors, a kind of immune checkpoint inhibitor, may thus comprise treatment options for the subgroups of patients exhibiting malignant progression driven by EMT activators [119].
MiR-205 (miR-205-5p) also suppresses EMT by targeting the ZEB1 and ZEB2 3′UTR [74]. Patients with NSCLC exhibiting low miR-205 expression had shorter relapse-free survival than those with high expression [120]. MiR-205 depletion releases the ZEB1 and SRC suppression (as both are miR-205 targets) and induces EGFR tyrosine kinase inhibitor resistance in EGFR mutant lung cancer [121].
MiR-455, a tumor suppressor, is significantly down-regulated in NSCLC tumor tissue samples and cell lines. MiR-455 (miR-455-3p) up-regulation inhibits cell proliferation, invasion, and migration by directly targeting ZEB1 [91]. Restoring ZEB1 rescues miR-455-induced suppression of tumor progression. MiR-33b inhibits cell growth, invasion, and EMT by suppressing Wnt/β-catenin/ZEB1 signaling [41]. MiR-1199-5p and ZEB1 form a reciprocal repressive feedback loop to potentially coordinate EMT and tumor metastasis [95]. MiR-101, miR-155-5p, and miR-199b, as tumor suppressors, inhibit EMT by targeting ZEB1 [54,67,77]. In turn, ZEB1 inactivates miRNAs by up-regulating competing RNAs (ceRNAs) or silencing the expression of TFs that drive miRNA expression [48,73]. The competing RNA-integrin α1 (ITGA1) competes with adenylyl cyclase 9 (ADCY9) for miR-181b. ZEB1 up-regulates ITGA1 to recruit miR-181b, thus relieving ADCY9 to drive metastasis in lung cancer cells [73]. ZEB1 also directly controls miR-203 and miR-200c transcription by directly binding to conserved E-boxes of their promoter regions [122]. Thus, a reciprocal negative feedback loop involving ZEB1 and miRNA expression may tightly control tumor metastasis.
ZEB2 also constitutes a direct target of miRNAs. Ectopic ZEB2 rescues the suppressed cell migration and invasion mediated by miR-132, which is significantly down-regulated in NSCLC cell lines and clinical NSCLC tissue samples. [42]. MiR-138, miR-145, miR-215, and miR-598 also suppress lung cancer cell invasion and migration by targeting ZEB2 [49,55,83,92].

3.3. Twist TF-Related miRNAs

Twist, an EMT TF, is a target of miR-98, as their expression levels inversely correlates in clinical NSCLC tissue specimens. MiR-98 up-regulation suppresses cell invasion and migration by impeding Twist-induced EMT [56]. Bioinformatics analysis and luciferase-reporter assay revealed that miR-92b suppresses Twist to reduce NSCLC metastasis [50]. MiR-33a targets Twist family BHLH transcription factor 1 (Twist 1) to inhibit NSCLC invasion and metastasis in vitro and in vivo [43].

3.4. MiRNAs Modulate Other EMT-Associated Signaling Genes and Related Downstream Proteins

Numerous EMT-associated signaling modulators are also regulated by miRNAs [123]. TGF-β, a well-known EMT activator, mediates cell proliferation, apoptosis, inflammation, tissue repair, and carcinogenesis [124]. Upon receptor binding, TGF-β induces receptor complex formation and activates downstream signals. TGF-β signaling includes Smad-dependent and Smad-independent pathways. In the former, Smad2/3/4 protein complex formation inhibits E-cadherin expression and induces fibronectin and matrix metalloprotease (MMP) expression, which regulates EMT processes. The latter involves RAS/RAF/ERK and PI3K/AKT signaling pathways, which are crucial for cell proliferation. [125,126]. Up-regulated TGF-β1 promotes lung adenocarcinoma invasion and metastasis via an EMT-associated mechanism [127]. Aberrant TGF-β up-regulation is critical to the development of targeted therapy resistance and disease progression in NSCLC [128,129,130,131]. MiRNAs target TGF-β pathway downstream factors to modulate EMT: miR-155 targets RhoA or Smad2/3, and miR-148a targets Rho-associated protein kinase I (ROCK1) [67,89,132]. MMPs digest most protein components in the ECM and participate in cell migration and invasion in physiological and pathological conditions, such as tissue remodeling and cancer cell progression [133].
NSCLC cells exhibit lower miR-148b expression than that in normal bronchial epithelial cells. A miR-148 mimic increased epithelial-associated E-cadherin and decreased mesenchymal-associated N-cadherin and vimentin expression. MiR-148b regulates ROCK1, a downstream TGF-β signaling factor, to inhibit cell proliferation and EMT, and increase sensitivity to radio-chemotherapy in NSCLC [93]. MiR-155-5p suppresses invasion and migration by targeting Smad2 [67]. MiR-215 represses NSCLC migration, invasion, and proliferation by directly targeting MMP-16 [134].
MiR-136 (miR-136-5p) inhibits lung cancer cell metastasis and EMT by directly targeting Smad2 and Smad3 [79]. Among a cohort of 1242 samples from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) datasets, miR-136-5p was up-regulated in lung adenocarcinoma versus normal tissues. Bioinformatics analysis using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Protein Analysis Through Evolutionary Relationships (PANTHER) pathways demonstrated that claudin-18, sialophorin, and syndecan 2, which function in cell adhesion and focal adhesion, likely comprise miR-136-5p target genes [135]. Because of the intrinsic complexity and sophistication of tumor initiation and progression, miR-136-5p might exhibit disparate dysregulation and functions in various cancers [135].
In NSCLC and hepatocellular carcinoma, MET oncogene activated miR-221 and miR-222 by activating the c-JUN TF. These miRNAs suppress phosphatase and tensin homolog (PTEN) and tissue inhibitor of metalloproteinases 3 (TIMP3), and promote cellular invasion and migration by activating the Akt (Protein kinase B, PKB) murine thymoma viral oncogene homolog (AKT) pathway and metallopeptidase [69]. Somatic PTEN mutation occurs in 4–8% of NSCLC [136,137], whereas PTEN overexpression inhibits lung cancer cell invasion and metastasis by inhibiting integrin αVβ6 signaling [138]. In patients with NSCLC, decreased PTEN expression constitutes a poor prognosis factor [139]. PTEN is also a target of miR-19 and miR-26a to regulate EMT in NSCLC [44,57]. MiR-664 regulates tumorigenesis and malignant progression in lung cancer cell lines, with up-regulated miR-664 promoting cell invasion and migration by targeting PTEN [102].
Transmembrane serine protease 4, a membrane-anchored protease, mediates cell invasion and migration in a variety of cancers including lung cancer. This protein suppresses miR-205 (miR-205-5p) expression to promote EMT. In vivo, miR-205-5p expression inhibits cell growth, migration, and metastasis formation. MiR-205-5p directly targets integrin α5, a pro-invasive protein in NSCLC. Down-regulated integrin α5 expression in lung cancer cells completely abrogates cell migration, decreases the fibronectin adherence capacity, and reduces tumor growth in vivo [52].
Polycomb repressive complex 2 subunit (SUZ12) is involved in NSCLC tumor progression by promoting cell proliferation and metastasis [140]. MiR-489 targets SUZ12 to modulate EMT. MiR-489 down-regulation decreases E-cadherin protein level and increases N-cadherin and vimentin, which promote NSCLC invasion [85]. MiR-302b-3p inhibits NSCLC progression by targeting glucosaminyl (N-acetyl) transferase 3 (GCNT3), with E-cadherin, N-cadherin, vimentin, phosphorylated-extracellular-signal-regulated kinase, and cyclin D1 being downstream molecules of the miR-302b-3p/GCNT3 pathway [72]. GCNT3 expression patterns are associated with different cancer progression [141,142]. MiR-105 promotes NSCLC EMT by up-regulating myeloid cell leukemia 1 (Mcl-1) [62]. MiR-21 is highly expressed in the serum of patients with NSCLC, whereas its depletion reduces A549 cell proliferation, migration, and invasion by up-regulating programmed cell death protein 4 (PDCD4) expression [51]. MiR-455-5p promotes cell proliferation and invasion by targeting suppressor of cytokine signaling 3 (SOCO3) in NSCLC, wherein aberrant miR-455-5p expression is partially controlled by ERK signaling activation [80].
MiRNAs exhibit contradictory effects on EMT because their targets are cell-context dependent. MiR-590 (miR-590-3p) promotes A549 lung adenocarcinoma cell migration and invasion by targeting olfactomedin 4 (OLFM4), inhibiting tumor cell adhesion [94]. Conversely, miR-590 (miR-590-5p) down-regulation promotes NSCLC cell migration and invasion because it directly targets disintegrin and metalloproteinase 9 (ADAM9) [97]. MiR-590 (miR-590-5p) overexpression inhibits NSCLC cell proliferation and invasion by directly targeting Grb2-associated binder 1 (GAB1) [98]. The discrepancy of cell invasion and migration in miR-590 comes from the different sequences between miR-590-3p and miR-590-5p.
In summary, the EMT plays a crucial role in tumor invasion and metastasis, and it is also complex, multifunctional, and tightly regulated developmental program. Accumulating evidence suggests that microRNAs tightly regulate EMT in lung cancer cells. MicroRNAs act as pro- or anti-EMT through different targets and signal pathways, which regulates lung cancer invasion and metastasis.

4. Role of miRNAs in Different Metastasis Sites (Bone, Brain and Lymph Nodes) in Lung Cancer

In addition to predicting patient survival and tumor relapse, patients with NSCLC with and without metastasis exhibit different miRNA profiles [143,144]. Numerous studies have investigated the association between miRNA expression profile and lung cancer metastatic sites [145] (Figure 2).

4.1. Role of miRNAs in Lung Cancer Bone Metastasis

Bone metastasis occurs in approximately 15 to 30 percent of patients with lung cancer [146], representing one of the most deleterious clinical consequences [147]. However, the exact mechanism of bone metastasis remains unknown. The miRNAs associated with lung cancer bone metastasis are listed in Table 2.
A high-throughput sequencing study to explore the candidate bone metastasis-related miRNAs in lung adenocarcinoma generated two small RNA (corresponding to 18–30 nucleotides) libraries from the blood of patients with lung adenocarcinoma with and without bone metastasis. Expression profiling revealed 7 down-regulated and 21 up-regulated miRNAs in lung adenocarcinoma with bone metastasis. Bioinformatics analysis identified putative associated signaling pathways including MAPK, Wnt, and nuclear factor kappa light chain enhancer of activated B cells (NF-κB), along with pathways involving cytoskeletal proteins, angiogenesis factors, and MMP [148].
Moreover, 18 patients with NSCLC and vertebral column metastasis exhibited higher miR-21 expression levels than that in 20 patients with bone tuberculosis [149]. MiR-21 promotes cell proliferation and inhibits apoptosis in H2170 NSCLC cells through overexpression of cytochrome C oxidase assembly homolog 19 (COX19) [149], which affects COX subunit assembly by increasing COX activity. Reducing COX activity increases cytochrome C content, activating cell apoptosis signaling pathways and finally leading to apoptosis [150,151]. MiR-21 also mediates tumorigenesis and osteoclastogenesis by targeting PDCD4, which regulates osteoclastogenesis [152].
Some viruses regulate their own and/or host gene expression via aberrant miRNA expression [153,154]. Microarray analysis to compare miRNA expression in bone metastasis (n = 10) from lung cancer with that of primary lung cancers (n = 24) identified and validated a candidate viral miRNA, Hsv2-miR-H9-5p, encoded by herpes simplex virus type 2 latency-associated transcript [155]. Hsv2-miR-H9-5p expression is significantly higher in bone metastasis lesions than primary lung cancers. Hsv2-miR-H9-5p increases lung cancer cell migration and invasion in vitro by directly targeting suppressor of cytokine signaling 2 (SOCS2), inhibiting Jak2 kinase activity and Jak2-signal transducer and activator of transcription 3 (STAT3) binding [156]. SOCS2 expression is down-regulated in lung cancer [157].
MiR-139-5p serum levels from patients with lung adenocarcinoma and osteolytic bone metastasis are lower than those in patients with other organ metastasis. MiR-139-5p expression in mesenchymal stem cells (MSCs) significantly increases during osteogenic differentiation. Notch homolog 1, translocation-associated (Drosophila) (Notch1), a direct miR-139-5p target, exhibits significant down-regulation during MSC osteogenesis [159]. Tumor transfer of miR-192-enriched exosome-like vesicles to the endothelial compartment of the osseous milieu in vivo reduced bone metastases burden. MiR-192 overexpression confers anti-osseous metastatic activity in vivo and limits tumor-induced angiogenesis [160]. MiR-203/TGF-β/Smad2 expression represents an important tumor suppressor signaling pathway for bone metastasis in NSCLC, as patients with bone metastasis exhibited lower tumor tissue miR-203 expression than those without bone metastasis [161].

4.2. Role of miRNAs in Lung Cancer Brain Metastasis

Brain metastasis affects approximately 25% of patients with NSCLC during their lifetime [162]. However, no molecular biomarkers or effective indices are available to reduce brain metastasis risk. The mechanism of brain metastasis is also not completely clear owing to the limited available tissue specimens. Table 3 lists lung cancer brain metastasis-related miRNAs.
MiRNA microarray-based comparison of expression profiles in five primary lung adenocarcinoma tumors versus three brain metastatic lung adenocarcinoma samples reveals obvious miR-145 down-regulation in brain metastatic samples, albeit no relationship between miR-145 and lymph node metastasis [163]. Among miRNAs from 527 patients with stage I NSCLC, miRNA microarray analysis identified 10 miRNAs associated with brain metastasis including miR-145 [164]. Promoter methylation-mediated miR-145-5p down-regulation promotes lung adenocarcinoma cell brain metastasis, whereas miR-145-5p expression reduces cancer cell migration [165].
MiR-21 is a target of STAT3 [179,180]. In patient-derived stem cell lines from lung-to-brain metastasis, miR-21 down-regulation attenuates brain metastasis-initiating cell self-renewal and migration comparably to STAT3 knockdown [166]. Compared to parental cells, miR-95-3p is down-regulated in brain metastasis cells generated through injection of lung adenocarcinoma cells into a left ventricle of nude mice. MiR-95-3p overexpression suppresses cell invasion, proliferation, and colony formation. Cyclin D1 was identified as a direct miR-95-3p target [167].
MiR-4317 is significantly down-regulated in tumor tissues compared with that in paired normal tissues, whereas patients with early stages and non-lymph node metastasis exhibit higher miR-4317 levels. MiR-4317 up-regulation significantly suppresses cell proliferation, colony formation, invasion, and migration. It also hampers NSCLC cell cycling by directly targeting fibroblast growth factor 9 (FGF9) and cyclin D2 (CCND2). In mouse xenograft model, miR-4317 suppresses tumor growth and brain and lung metastasis [178]. MiRNA microarray analysis identified miR-328 as related to brain metastasis by comparing samples from patients with (n = 7) and without (n = 8) brain metastasis. MiR-328 overexpression in A549 cells significantly promotes cell migration concomitant with protein kinase C alpha (PRKCA) up-regulation [171].
Overexpression of mir-423-5p, selected using microarray analysis of brain metastasis-related miRNAs and validated by quantitative PCR, promotes NSCLC cell colony formation, cell motility, migration, and invasion by direct targeting metastasis suppressor 1 (MTSS1). In clinical samples, lung adenocarcinoma tissues without brain metastasis exhibit positive staining for MTSS1 expression [176]. Microarray analysis between patients with and without brain metastasis revealed that a three-miRNA (including miR-210, miR-214, and miR-15a) signature predicts the brain metastasis of patients with lung adenocarcinoma with high sensitivity and specificity [170].
Recently, increasing evidence revealed that exosomes play important roles in the tumor microenvironment and the mechanism of malignant tumor metastasis. Exosomes, consist of a phospholipid bilayer, which is composed mainly of proteins, lipids, carbohydrates, and nucleic acids [181,182]. Exosome carries miRNAs, termed “exomiRs”, to acceptor cells to promote non-adjacent intercellular communication, which involves in cell differentiation, immune response, antigen presentation, and cell invasion/migration [183,184,185]. The transfer of exosomal miRNA can modulate gene expression in acceptor cancer cells to facilitate metastasizing cancer cell settlement in pre-metastatic organs, suggesting these exosomal miRNAs prepare the pre-metastatic niche [186].
Astrocytes oppose brain metastasis via exosome-delivered miR-142-3p, which directly binds to the suppressing transient receptor potential ankyrin-1 (TRPA1) 3′UTR. TRPA1 also directly targets the FGF receptor 2 C-terminal proline-rich motif, thereby constitutively activating the receptor and increasing lung adenocarcinoma progression and metastasis [168]. Transferring miR-142-3p from astrocytes to lung cancer cells suppresses TRPA1 in the latter, promoting brain metastasis. MiR-184 and miR-197 are also overexpressed in patients carrying EGFR mutation with brain metastasis; their expression level may serve to stratify the brain metastasis risk in this subpopulation [169].

4.3. Role of miRNAs in Lung Cancer Lymph Node Metastasis

Lymphatic metastasis comprises an important mechanism in tumor spreading in addition to metastasis via blood vessels. The primary epithelial cancer cells enter into the lymphatic drainage system and spread to local or distal lymph nodes after penetrating the basement membrane [187]. For patients with early stage lung cancer, lymphatic invasion or lymph node involvement represents a key prognostic factor. Regional lymph node status is important for lung cancer staging and treatment planning [188]. However, traditional image examination (chest CT) sensitivity is poor. Micro-metastasis or occult lymph node metastasis is still found in approximately 20% of early stage (T1/T2) lung cancer tumors [189,190]. Positron emission tomography (PET) scanning and endobronchial ultrasound-guided transbronchial needle aspiration can decrease the high false-negative rate and provide greater sensitivity and specificity for mediastinal lymph node assessment [191,192,193]. The identification of molecular biomarkers expressed in tumor tissue or patient serum is helpful to predict lymph node metastasis. Table 4 lists the different miRNAs related to lymph node metastasis.
The role of miR-200c in lung cancers is controversial. MiR-200c inhibits NSCLC cells invasion and migration, and expression of the miR-200c targets USP25 in NSCLC correlates with clinical stage and lymphatic node metastasis [115]. Lower miR-200c expression also significantly correlates with poor differentiation grade, lymph node metastasis, and lower E-cadherin expression [115,275]. However, higher tumor miR-200c expression was reportedly associated with poor survival in patients with NSCLC [209,276].
MiR-125a-3p/5p is down-regulated in NSCLC tissues compared with adjacent normal lung tissues. However, the relationship with metastasis differs between the two mature miRNAs, which are derived from the 3′ and 5′ ends of pre-miR-125a. Patients with low miR-125a-3p and high miR-125a-5p expression exhibit increased lymph node metastasis [235]. A similar correlation is reported between miR-125a-3p and lymph node metastasis [236]. Alternatively, miR-125a-5p overexpression inhibits lung adenocarcinoma cell proliferation and induces cell apoptosis by targeting neural precursor cell expressed, developmentally down-regulated 9 (NEDD9). MiR-125a-5p expression negatively correlates with lymph node metastasis [237]. In turn, miR-125b exhibits tumor suppressor function by targeting MMP-13 to inhibit cell invasion. Decreasing miR-125b in tumor tissues correlates with lymph node metastasis [238].
MiR-130 also plays a controversial role in NSCLC. MiR-130 is significantly down-regulated in NSCLC tumor tissues and cell lines. High miR-130 expression inversely correlates with lymph node metastasis and late stages. MiR-130 up-regulation significantly suppresses NSCLC cell growth and enhances cell apoptosis by directly targeting PTEN [243]. MiR-130 family consists of miR-130a and miR-130b, and they have nearly identical sequences, although miR-130a and miR-130b come from chromosome 11 and chromosome 22, respectively. MiR-130a functions as a proangiogenic miRNA and antagonizes the inhibitory effect of growth arrest homeobox transcription factor and homeobox A5 (HoxA5) on endothelial cell proliferation, migration, and tube formation [338]. MiR-130a is also overexpressed in NSCLC tissues, with higher expression being strongly associated with lymph node metastasis and poor prognosis [244]. Further studies are thus needed to clarify the role of miR-130 in NSCLC.
Serum miRNA levels also serve as biomarkers of NSCLC metastasis or prognosis [209,213]. High serum miR-21 correlates with advanced stages and lymph node metastasis. MiR-21 promotes cell proliferation, metastasis, and chemo-radio-resistance in NSCLC cells by targeting PTEN [211]. High serum miR-19a and miR-19b also significantly correlate with tumor-node-metastasis (TNM) stage and lymph node metastasis [207,208]. Patients with NSCLC exhibit significantly increased serum miR-494 levels compared with those in healthy controls, with the levels markedly decreasing when patients receive effective therapy. MiR-494 up-regulation in serum or tumor tissues significantly associates with higher incidence of lymph node metastasis, advanced clinical stage, and higher histological grade [317,318]. MiR-210, miR-421, and miR-411 levels in tumor tissues or serum of patients with lung cancer significantly positively correlate with lymph node metastasis and poor prognosis [279,280,300,301]. Patients with NSCLC exhibit lower serum miR-138 than that of healthy controls. Low miR-138 expression correlates with positive lymph node metastasis and poor prognosis [248]. MiR-138 suppresses NSCLC proliferation, metastasis, and autophagy by targeting sirtuin 1 (Sirt1) [249]. MiR-138 also targets Yes-associated protein 1 (YAP1) [250].
MiRNAs are detected in sputum and plasma [313]. Between lung cancer tissues with adjacent non-cancerous specimens, the former show lower miR-486-5p expression, with the reduced expression being associated with advanced clinical stage and lymph node metastasis of NSCLC [312,313,314]. In vitro, miR-486-5p down-regulation promotes tumor progression and metastasis by targeting Rho GTPase-activating protein 5 (ARHGAP5). MiR-486-5p expression in sputum and plasma specimens could provide a diagnostic approach for early lung cancer detection [314]. Moreover, miR-486-5p up-regulation in cancer cells reduces expression of Pim-1, a direct target. Pim-1 kinase, a proto-oncogene, is overexpressed in 66.2% of lung tumor tissues by immunohistochemical staining. Pim-1 expression is significantly higher in NSCLC tissues than in adjacent normal tissues [315].
Meta-analysis from the TCGA database demonstrated that lower miR-133a-3p correlates with negative lymph node metastasis and might act as a tumor suppressor [245]. In lung adenocarcinoma, miR-452-5p expression is obviously lower than that in adjacent normal tissues, and negatively correlates with lymph node metastasis and TNM stage [310]. MiR-145-5p shows similar findings among 125 paired NSCLC tissues and the TCGA database, indicating that both miRNAs function as tumor suppressors [255]. Among 372 NSCLC and 42 adjacent normal lung tissues from the Gene Expression Omnibus dataset, miR-101-3p showed higher expression in normal than NSCLC tumor tissues. Low miR-101-3p expression significantly correlated with lymph node metastasis and shorter OS [228].
Gene promoter methylation generally results in down-regulation of gene expression. Aberrant miR-200c promoter methylation obviously negatively correlates with miR-200c expression and is associated with lymph node metastasis and poor clinical outcome [275]. Histone methylation-mediated (H3K27me3) miR-139 silencing enhances NSCLC invasive and metastatic phenotype, with down-regulated miR-139 expression being significantly associated with lymph node metastasis and tumor invasiveness [251].
MiRNAs are also influenced by other non-coding RNAs, such as long noncoding RNA (lncRNA), which are over 200 nucleotides in length and exert their effects in the form of RNA. The lncRNA LINC00978 promotes cell proliferation and invasion in NSCLC by inhibiting miR-6754-5p [337]. HOXD-AS1 promotes NSCLC migration and invasion by regulating the miR-133b/MMP9 axis, with miR-133b being a direct target of HOXD-AS1 in NSCLC [247]. LncRNA NNT-AS1 promotes lung cancer cell proliferation and invasion by regulating miR-129-5p [242]. LncRNA SNHG15 promotes NSCLC proliferation and migration by targeting miR-211-3p, with high SNHG15 expression levels correlating with tumor size and lymph node metastasis [281]. LncRNA HNF1A-AS1 promotes cell proliferation and invasion by directly targeting miR-17-5p in NSCLC [205]. HOXA11-AS acts as a ceRNA to regulate TF Sp1 expression via sponging miR-124 [234]. NEAT1 promotes proliferation and invasion by targeting miR-181a-5p [264]. LncRNA XLOC_008466 functions as an oncogene in NSCLC by regulating the miR-874-MMP2/XIAP axis. XLOC_008466 up-regulation in patients with NSCLC was related to lymph node metastasis and TNM stage [331]. LncRNA SNHG1 overexpression promotes NSCLC progression by inhibiting miR-101-3p and activating the Wnt/β-catenin signaling pathway [229]. More examples can be found in recent reviews [339,340].

5. Potential of miRNA as a Therapeutic Target and Tool in Patients with Lung Cancer

Increasing evidence demonstrates that miRNAs play pivotal roles in lung cancer invasion and metastasis. Studies using miRNA profiling to predict prognosis and clinical treatment response indicate that miRNA expression profiles can predict patient cancer relapse and clinical outcome in NSCLC [143]. The European Lung Cancer Working Party (ELCWP) prospective study, initiated to identify a miRNA-based signature for treatment response and survival for NSCLC treated with cisplatin and vinorelbine, revealed that a four-miRNA signature (miR-200c, miR-424, miR-29c, and miR-124) could predict treatment response of first-line cisplatin and vinorelbine and act as a prognostic factor in patients with NSCLC [341]. The combination of a plasma immune-related microRNA-signature classifier and immunohistochemical stain of programmed death-ligand 1 in tumor specimens could predict poor treatment response and OS in patients with NSCLC treated with immune-checkpoint inhibitors [342].
For predicting disease prognosis, gain- and loss-of-function studies of miRNAs have provided a rationale and innovative insight toward precision medicine by targeting miRNA to prevent tumor progression or spreading of cancer cells, because miRNAs can stably modulate gene networks [343]. Possible approaches include: (i) miRNA-based treatment (Direct strategy). Introduction of synthetic miRNA analogs (miR mimics) to mimic tumor suppressor miRNAs that are down-regulated in cancer cells, or antisense oligonucleotides (known as anti-miRs or antagomiR) to silence oncogenic/metastasis-promoting miRNAs [344,345]. Although ectopic expression of synthetic miRNAs mimics was accomplished in vitro, there was little in vivo data using miRNA mimics delivered by intravenous injection. The expression of miRNAs is also restored by inserting genes coding for miRNAs into viral constructs, such as the adenovirus-associated vectors (AAV) [346,347,348]. These vectors do not integrate into the genome and have high efficiency of transduction. Kota and colleagues cloned miR-26a into an AAV vector and viral particles were tested in a mouse model of liver cancer. Systemic administration of miR-26a results in inhibition of cancer cell proliferation, induction of tumor-specific apoptosis, and dramatic protection from disease progression without toxicity [348]. Besides, miRNA-based treatment involves various strategies, including miR-mask and miRNA sponges which interrupt the interaction between target and miRNAs [346]. (ii) Induction of miRNA expression (Indirect strategy). Some drugs were developed to modulate the expression of miRNAs by regulating activation or repression of upstream transcription factors. By screening for more than 1000 small molecular compounds, diazobenzene 1 promoted transcription of miR-21 and produced a 250% increase of miR-21 relative to the untreated cells [349].
A critical challenge of targeted miRNA therapy is how to introduce the synthetic oligonucleotide or miRNA mimic into the cancer cells. Viral and non-viral vectors comprise commonly used vectors for miRNA delivery [350]. However, viral vector introduction into the host system can trigger an immune response [351]. Systemic treatment with miR-10b antagomir, a 2’-O-methyl-group (OMe)-modified, cholesterol-conjugated antisense miR, and miR-34a mixed with atelocollagen could suppress breast and colon cancer metastasis, respectively, in animal studies [352,353]. Systemic delivery of miR-34a into experimental lung metastasis of murine B16F10 melanoma using a liposome-polycation-hyaluronic acid nanoparticle formulation modified with tumor-targeting single chain antibody fragment (scFv) reduces tumor load in the lung [354].
Several pre-clinical and clinical trials of miRNA as targeting therapy for lung cancer are ongoing (Table 5). Let-7 suppresses lung tumor via KRAS in vivo, and exogenous lentivirus-mediated let-7 delivery significantly reduces the tumor burden in mouse models of NSCLC [355]. Systemic let-7 or miR-34a delivery by injection of neutral lipid emulsion also significantly attenuates tumor burden in the KRAS autochthonous NSCLC mouse model [272,356]. For EGFR mutant NSCLC, combinatorial treatment with let-7b and miR-34a provides synergistic treatment effect with erlotinib, an EGFR tyrosine kinase inhibitor, to suppress NSCLC proliferation [357]. Plasmid-mediated miR-126 plasmid inhibits A549 cell proliferation in vitro and inhibits tumor growth in vivo by increasing expression of EFG–like domain 7 [358]. MiR-145 inhibits NSCLC proliferation by directly targeting c-Myc in vitro [359]. Cationic polyurethane-short branch polyethylenimine (PEI) -mediated delivery of miR-145 inhibits xenograft tumor growth, EMT, and metastasis, and prolongs the survival times of a lung adenocarcinoma mouse model [360]. Efficient systemic delivery of miR-133-b and miR-29 by cationic lipoplexes inhibits tumor growth in vitro and in vivo [361,362]. The first miRNA mimic-based therapy, MRX34 (Mirna Therapeutics Inc., Austin, TX, USA.), a liposomal miR-34 mimic, entered phase I clinical trial of liver cancer therapy in 2013 [363], demonstrating acceptable safety and antitumor activity of MRX34 in a subset of patients with refractory advanced solid tumors [364], along with positive results of lung cancer in vitro and in animal studies [356,365]. However, the further phase I/II clinical trials (ClinicalTrials.gov identifiers: NCT01829971, NCT02862145) were terminated or withdrawn because the suitability of associated serious immune-related adverse events for clinical application was questioned.
MesomiR 1 (NCT02369198), a first-in-man, phase I clinical trial, enrolled patients with NSCLC and malignant pleural mesothelioma to assess the safety and activity of TargomiRs as the second and third line of treatment [367]. TargomiRs (TargomiRs; EnGeneIC Ltd., Sydney, Australia) comprise minicells loaded with a miR-16-based mimic, which acts as an anti-EGFR specific antibody. The MesomiR 1 study intended to specifically deliver miR-16 to suppress tumor development, as the family of this miRNA is associated with tumor suppression in several cancers. The clinical trial demonstrated the acceptable safety profile in patients with malignant pleural mesothelioma [366]. Future research is necessary to address clinical treatment efficacy.
Argonaute-2 (AGO2) mediates post-transcriptional gene silencing, as an essential component of the RNA-induced silencing complex (RISC). After miRNA assembles into RISC, the activation complex silences and degrades the target mRNA transcripts [368]. However, when a double-strand RNA loads into AGO2, the AGO2-bound RNAs can activate transcription in the nucleus, paradoxically increasing mRNA expression [343,369]. According to this mechanism, a phase 1 trial (NCT02716012) of hepatocellular carcinoma was launched for a small activating RNA (saRNA) drug to increase CCAAT/enhancer-binding protein α (C/EBPα) expression. The dsp21 (saRNA) is designed to activate p21WAF1/CIP1 gene expression, and it inhibits cell proliferation, and induces apoptosis in lung cancer H441 and A549 cells [370,371]. More importantly, dsp21 increased the chemo-sensitivity to cisplatin of lung cancer cells in vitro and in vivo [371]. This synergistic effect of saRNA and chemotherapy may provide a reasonable concept for developing a treatment strategy in lung cancers. In addition to chemotherapy, aberrant activity of oncogenic pathways are the characteristics of carcinogenesis, it is worth noting that the combined treatment strategy of miRNA and saRNA to concurrently silence and activate opposing pathways of cancer. The combination strategies may develop more potent precision therapies of cancers [372].
There are several advantages of miRNA-based therapeutic in lung cancer over other treatment strategies, such as targeting growth factor receptors or enzymatic proteins. MiRNA-based therapies have emerged as promising therapeutic tools for cancer management due to highly specific in tissues and tumors. In addition, the advantage of using miRNA approaches is based on the ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation, and survival. Therefore, miRNAs therapies have extremely efficiencies in regulating distinct biological cell processes relevant to malignant cell homeostasis [346,373]. The ability of miRNAs to regulate multiple genes in a molecular pathway makes them excellent candidates for novel molecular-targeting treatments.
However, there are still some problems with miRNA therapies. Therapeutic miRNAs is difficult to cross through cell membranes resulting in poor cellular uptake of oligonucleotides because of the size and negative charge of miRNAs. In addition, delivering a therapeutic miRNA to the associated target tissues also challenges. MiRNAs are relatively unstable and reduce their half-life substantially in the blood circulation due to subject to rapid degradation by RNases [272]. It is an obstacle to achieve a sufficient amount of synthetic oligonucleotides to sustain the inhibitory effect [346,374,375]. Finally, the potential off-target effects of miRNA therapeutics are major concerns because of concurrent regulation of many genes. In addition, recent reports revealed the toxicity related to miRNA therapies [376]. These pharmacokinetic and pharmacological drawbacks of RNA-based therapeutics, such as off-targeting, low serum stability, and innate immune responses, require more research.
Although miRNA replacement therapy remains challenging with numerous problems needing to be resolved, several clinical trials with miRNA mimics have already been initiated. By developing more specific carriers and expression models, regulation of miRNA function will likely become more specific and effective for cancers. Cancer therapy through miRNA regulation may thus engender a new era for cancer patients in the near future.

6. Conclusions

Lung cancer remains a major cause of cancer-associated deaths globally. The aggressive behavior of lung cancer involved in invasion and migration caused disease rapid progression despite standard treatment. MiRNAs regulate multiple genes and different signal pathways. Increasing studies suggested that miRNAs reveal discrete expression patterns in lung cancers. Dysregulation of miRNA expression regulates EMT and cancer metastasis by targeting various genes. Different miRNA expression in tumor tissues or sera is associated with different metastatic sites. These miRNA profiles also correlate with prognosis and clinical treatment response in lung cancers and could be potential targets of lung cancer treatment. More research on miRNA targeted therapies is necessary to increase the target specificity and potency and decrease the off-target effects and toxicity. Exploring miRNA-targeted therapy may establish a new spectrum of lung cancer treatments.

Author Contributions

S.-G.W. writing—original draft preparation, T.-H.C., Y.-N.L. and J.-Y.S. writing—review and editing.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 2018, 68, 7–30. [Google Scholar] [CrossRef] [PubMed]
  2. The National Lung Screening Trial Research Team; Church, T.R.; Black, W.C.; Aberle, D.R.; Berg, C.D.; Clingan, K.L.; Duan, F.; Fagerstrom, R.M.; Gareen, I.F.; Gierada, D.S.; et al. Results of initial low-dose computed tomographic screening for lung cancer. N. Engl. J. Med. 2013, 368, 1980–1991. [Google Scholar] [CrossRef] [PubMed]
  3. Thiery, J.P.; Acloque, H.; Huang, R.Y.; Nieto, M.A. Epithelial-mesenchymal transitions in development and disease. Cell 2009, 139, 871–890. [Google Scholar] [CrossRef] [PubMed]
  4. Krol, J.; Loedige, I.; Filipowicz, W. The widespread regulation of microRNA biogenesis, function and decay. Nat. Rev. Genet. 2010, 11, 597–610. [Google Scholar] [CrossRef] [PubMed]
  5. Lu, J.; Getz, G.; Miska, E.A.; Alvarez-Saavedra, E.; Lamb, J.; Peck, D.; Sweet-Cordero, A.; Ebert, B.L.; Mak, R.H.; Ferrando, A.A.; et al. MicroRNA expression profiles classify human cancers. Nature 2005, 435, 834–838. [Google Scholar] [CrossRef] [PubMed]
  6. Lagos-Quintana, M.; Rauhut, R.; Yalcin, A.; Meyer, J.; Lendeckel, W.; Tuschl, T. Identification of tissue-specific microRNAs from mouse. Curr. Biol. 2002, 12, 735–739. [Google Scholar] [CrossRef]
  7. Calin, G.A.; Croce, C.M. MicroRNA signatures in human cancers. Nat. Rev. Cancer 2006, 6, 857–866. [Google Scholar] [CrossRef] [PubMed]
  8. Ruvkun, G. Clarifications on miRNA and cancer. Science 2006, 311, 36–37. [Google Scholar] [CrossRef] [PubMed]
  9. Stahlhut, C.; Slack, F.J. MicroRNAs and the cancer phenotype: Profiling, signatures and clinical implications. Genome Med. 2013, 5, 111. [Google Scholar] [CrossRef] [PubMed]
  10. Choudhury, Y.; Tay, F.C.; Lam, D.H.; Sandanaraj, E.; Tang, C.; Ang, B.T.; Wang, S. Attenuated adenosine-to-inosine editing of microRNA-376a* promotes invasiveness of glioblastoma cells. J. Clin. Investig. 2012, 122, 4059–4076. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  11. Bui, N.; Woodward, B.; Johnson, A.; Husain, H. Novel Treatment Strategies for Brain Metastases in Non-small-cell Lung Cancer. Curr. Treat. Options Oncol. 2016, 17, 25. [Google Scholar] [CrossRef] [PubMed]
  12. Jiang, W.G.; Sanders, A.J.; Katoh, M.; Ungefroren, H.; Gieseler, F.; Prince, M.; Thompson, S.K.; Zollo, M.; Spano, D.; Dhawan, P.; et al. Tissue invasion and metastasis: Molecular, biological and clinical perspectives. Semin. Cancer Biol. 2015, 35, S244–S275. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Woodhouse, E.C.; Chuaqui, R.F.; Liotta, L.A. General mechanisms of metastasis. Cancer 1997, 80, 1529–1537. [Google Scholar] [CrossRef]
  14. Cheung, K.J.; Ewald, A.J. A collective route to metastasis: Seeding by tumor cell clusters. Science 2016, 352, 167–169. [Google Scholar] [CrossRef] [PubMed]
  15. Thiery, J.P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2002, 2, 442–454. [Google Scholar] [CrossRef] [PubMed]
  16. Kalluri, R.; Weinberg, R.A. The basics of epithelial-mesenchymal transition. J. Clin. Investig. 2009, 119, 1420–1428. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Yang, J.; Weinberg, R.A. Epithelial-mesenchymal transition: At the crossroads of development and tumor metastasis. Dev. Cell 2008, 14, 818–829. [Google Scholar] [CrossRef] [PubMed]
  18. Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell 2000, 100, 57–70. [Google Scholar] [CrossRef]
  19. Acloque, H.; Adams, M.S.; Fishwick, K.; Bronner-Fraser, M.; Nieto, M.A. Epithelial-mesenchymal transitions: The importance of changing cell state in development and disease. J. Clin. Investig. 2009, 119, 1438–1449. [Google Scholar] [CrossRef] [PubMed]
  20. Kalluri, R.; Neilson, E.G. Epithelial-mesenchymal transition and its implications for fibrosis. J. Clin. Investig. 2003, 112, 1776–1784. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  21. Edme, N.; Downward, J.; Thiery, J.P.; Boyer, B. Ras induces NBT-II epithelial cell scattering through the coordinate activities of Rac and MAPK pathways. J. Cell Sci. 2002, 115, 2591–2601. [Google Scholar] [PubMed]
  22. Jenndahl, L.E.; Isakson, P.; Baeckstrom, D. c-erbB2-induced epithelial-mesenchymal transition in mammary epithelial cells is suppressed by cell-cell contact and initiated prior to E-cadherin downregulation. Int. J. Oncol. 2005, 27, 439–448. [Google Scholar] [CrossRef] [PubMed]
  23. Jeon, H.M.; Lee, J. MET: Roles in epithelial-mesenchymal transition and cancer stemness. Ann. Transl. Med. 2017, 5, 5. [Google Scholar] [CrossRef] [PubMed]
  24. Webb, C.P.; Taylor, G.A.; Jeffers, M.; Fiscella, M.; Oskarsson, M.; Resau, J.H.; Vande Woude, G.F. Evidence for a role of Met-HGF/SF during Ras-mediated tumorigenesis/metastasis. Oncogene 1998, 17, 2019–2025. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Wise, R.; Zolkiewska, A. Metalloprotease-dependent activation of EGFR modulates CD44(+)/CD24(-) populations in triple negative breast cancer cells through the MEK/ERK pathway. Breast Cancer Res. Treat. 2017, 166, 421–433. [Google Scholar] [CrossRef] [PubMed]
  26. Claperon, A.; Mergey, M.; Nguyen Ho-Bouldoires, T.H.; Vignjevic, D.; Wendum, D.; Chretien, Y.; Merabtene, F.; Frazao, A.; Paradis, V.; Housset, C.; et al. EGF/EGFR axis contributes to the progression of cholangiocarcinoma through the induction of an epithelial-mesenchymal transition. J. Hepatol. 2014, 61, 325–332. [Google Scholar] [CrossRef] [PubMed]
  27. Mamuya, F.A.; Duncan, M.K. aV integrins and TGF-beta-induced EMT: A circle of regulation. J. Cell. Mol. Med. 2012, 16, 445–455. [Google Scholar] [CrossRef] [PubMed]
  28. Shi, Y.; Massague, J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003, 113, 685–700. [Google Scholar] [CrossRef]
  29. Kokudo, T.; Suzuki, Y.; Yoshimatsu, Y.; Yamazaki, T.; Watabe, T.; Miyazono, K. Snail is required for TGFbeta-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells. J. Cell Sci. 2008, 121, 3317–3324. [Google Scholar] [CrossRef] [PubMed]
  30. Jechlinger, M.; Grunert, S.; Beug, H. Mechanisms in epithelial plasticity and metastasis: Insights from 3D cultures and expression profiling. J. Mammary Gland Biol. Neoplasia 2002, 7, 415–432. [Google Scholar] [CrossRef] [PubMed]
  31. Moustakas, A.; Heldin, C.H. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci. 2007, 98, 1512–1520. [Google Scholar] [CrossRef] [PubMed]
  32. Kim, Y.S.; Yi, B.R.; Kim, N.H.; Choi, K.C. Role of the epithelial-mesenchymal transition and its effects on embryonic stem cells. Exp. Mol. Med. 2014, 46, e108. [Google Scholar] [CrossRef] [PubMed]
  33. Kim, N.H.; Kim, H.S.; Li, X.Y.; Lee, I.; Choi, H.S.; Kang, S.E.; Cha, S.Y.; Ryu, J.K.; Yoon, D.; Fearon, E.R.; et al. A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition. J. Cell Biol. 2011, 195, 417–433. [Google Scholar] [CrossRef] [PubMed]
  34. Jia, Z.; Zhang, Y.; Xu, Q.; Guo, W.; Guo, A. miR-126 suppresses epithelial-to-mesenchymal transition and metastasis by targeting PI3K/AKT/Snail signaling of lung cancer cells. Oncol. Lett. 2018, 15, 7369–7375. [Google Scholar] [CrossRef] [PubMed]
  35. Sun, C.C.; Li, S.J.; Yuan, Z.P.; Li, D.J. MicroRNA-346 facilitates cell growth and metastasis, and suppresses cell apoptosis in human non-small cell lung cancer by regulation of XPC/ERK/Snail/E-cadherin pathway. Aging (Albany N. Y.) 2016, 8, 2509–2524. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Zhang, K.; Li, X.Y.; Wang, Z.M.; Han, Z.F.; Zhao, Y.H. MiR-22 inhibits lung cancer cell EMT and invasion through targeting Snail. Eur. Rev. Med. Pharmacol. Sci. 2017, 21, 3598–3604. [Google Scholar] [PubMed]
  37. Fan, M.J.; Zhong, Y.H.; Shen, W.; Yuan, K.F.; Zhao, G.H.; Zhang, Y.; Wang, S.K. MiR-30 suppresses lung cancer cell 95D epithelial mesenchymal transition and invasion through targeted regulating Snail. Eur. Rev. Med. Pharmacol. Sci. 2017, 21, 2642–2649. [Google Scholar] [PubMed]
  38. Kumarswamy, R.; Mudduluru, G.; Ceppi, P.; Muppala, S.; Kozlowski, M.; Niklinski, J.; Papotti, M.; Allgayer, H. MicroRNA-30a inhibits epithelial-to-mesenchymal transition by targeting Snai1 and is downregulated in non-small cell lung cancer. Int. J. Cancer 2012, 130, 2044–2053. [Google Scholar] [CrossRef] [PubMed]
  39. Hu, W.W.; Chen, P.C.; Chen, J.M.; Wu, Y.M.; Liu, P.Y.; Lu, C.H.; Lin, Y.F.; Tang, C.H.; Chao, C.C. Periostin promotes epithelial-mesenchymal transition via the MAPK/miR-381 axis in lung cancer. Oncotarget 2017, 8, 62248–62260. [Google Scholar] [CrossRef] [PubMed]
  40. Tominaga, E.; Yuasa, K.; Shimazaki, S.; Hijikata, T. MicroRNA-1 targets Slug and endows lung cancer A549 cells with epithelial and anti-tumorigenic properties. Exp. Cell Res. 2013, 319, 77–88. [Google Scholar] [CrossRef] [PubMed]
  41. Qu, J.; Li, M.; An, J.; Zhao, B.; Zhong, W.; Gu, Q.; Cao, L.; Yang, H.; Hu, C. MicroRNA-33b inhibits lung adenocarcinoma cell growth, invasion, and epithelial-mesenchymal transition by suppressing Wnt/beta-catenin/ZEB1 signaling. Int. J. Oncol. 2015, 47, 2141–2152. [Google Scholar] [CrossRef] [PubMed]
  42. You, J.; Li, Y.; Fang, N.; Liu, B.; Zu, L.; Chang, R.; Li, X.; Zhou, Q. MiR-132 suppresses the migration and invasion of lung cancer cells via targeting the EMT regulator ZEB2. PLoS ONE 2014, 9, e91827. [Google Scholar] [CrossRef] [PubMed]
  43. Yang, L.; Yang, J.; Li, J.; Shen, X.; Le, Y.; Zhou, C.; Wang, S.; Zhang, S.; Xu, D.; Gong, Z. MircoRNA-33a inhibits epithelial-to-mesenchymal transition and metastasis and could be a prognostic marker in non-small cell lung cancer. Sci. Rep. 2015, 5, 13677. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Li, J.; Yang, S.; Yan, W.; Yang, J.; Qin, Y.J.; Lin, X.L.; Xie, R.Y.; Wang, S.C.; Jin, W.; Gao, F.; et al. MicroRNA-19 triggers epithelial-mesenchymal transition of lung cancer cells accompanied by growth inhibition. Lab. Investig. 2015, 95, 1056–1070. [Google Scholar] [CrossRef] [PubMed]
  45. Xia, Y.; Zhu, Y.; Ma, T.; Pan, C.; Wang, J.; He, Z.; Li, Z.; Qi, X.; Chen, Y. miR-204 functions as a tumor suppressor by regulating SIX1 in NSCLC. FEBS Lett. 2014, 588, 3703–3712. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Cui, Z.; Hu, Y. MicroRNA-124 suppresses Slug-mediated lung cancer metastasis. Eur. Rev. Med. Pharmacol. Sci. 2016, 20, 3802–3811. [Google Scholar] [PubMed]
  47. Hu, F.Y.; Cao, X.N.; Xu, Q.Z.; Deng, Y.; Lai, S.Y.; Ma, J.; Hu, J.B. miR-124 modulates gefitinib resistance through SNAI2 and STAT3 in non-small cell lung cancer. J. Huazhong Univ. Sci. Technol. Med. Sci. 2016, 36, 839–845. [Google Scholar] [CrossRef] [PubMed]
  48. Ahn, Y.H.; Gibbons, D.L.; Chakravarti, D.; Creighton, C.J.; Rizvi, Z.H.; Adams, H.P.; Pertsemlidis, A.; Gregory, P.A.; Wright, J.A.; Goodall, G.J.; et al. ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression. J. Clin. Investig. 2012, 122, 3170–3183. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Jin, Z.; Guan, L.; Song, Y.; Xiang, G.M.; Chen, S.X.; Gao, B. MicroRNA-138 regulates chemoresistance in human non-small cell lung cancer via epithelial mesenchymal transition. Eur. Rev. Med. Pharmacol. Sci. 2016, 20, 1080–1086. [Google Scholar] [PubMed]
  50. Liu, X.; Tian, X.D.; Liu, Y.; Zhang, T.; Chen, L. Regulation of Twist in the metastasis of non-small cell lung cancer by miR-92b. Eur. Rev. Med. Pharmacol. Sci. 2016, 20, 4003–4010. [Google Scholar] [PubMed]
  51. Yang, Y.; Meng, H.; Peng, Q.; Yang, X.; Gan, R.; Zhao, L.; Chen, Z.; Lu, J.; Meng, Q.H. Downregulation of microRNA-21 expression restrains non-small cell lung cancer cell proliferation and migration through upregulation of programmed cell death 4. Cancer Gene Ther. 2015, 22, 23–29. [Google Scholar] [CrossRef] [PubMed]
  52. Larzabal, L.; de Aberasturi, A.L.; Redrado, M.; Rueda, P.; Rodriguez, M.J.; Bodegas, M.E.; Montuenga, L.M.; Calvo, A. TMPRSS4 regulates levels of integrin alpha5 in NSCLC through miR-205 activity to promote metastasis. Br. J. Cancer 2014, 110, 764–774. [Google Scholar] [CrossRef] [PubMed]
  53. Chang, T.H.; Tsai, M.F.; Gow, C.H.; Wu, S.G.; Liu, Y.N.; Chang, Y.L.; Yu, S.L.; Tsai, H.C.; Lin, S.W.; Chen, Y.W.; et al. Upregulation of microRNA-137 expression by Slug promotes tumor invasion and metastasis of non-small cell lung cancer cells through suppression of TFAP2C. Cancer Lett. 2017, 402, 190–202. [Google Scholar] [CrossRef] [PubMed]
  54. Han, L.; Chen, W.; Xia, Y.; Song, Y.; Zhao, Z.; Cheng, H.; Jiang, T. MiR-101 inhibits the proliferation and metastasis of lung cancer by targeting zinc finger E-box binding homeobox 1. Am. J. Transl. Res. 2018, 10, 1172–1183. [Google Scholar] [PubMed]
  55. Liu, Q.; Chen, J.; Wang, B.; Zheng, Y.; Wan, Y.; Wang, Y.; Zhou, L.; Liu, S.; Li, G.; Yan, Y. miR-145 modulates epithelial-mesenchymal transition and invasion by targeting ZEB2 in non-small cell lung cancer cell lines. J. Cell. Biochem. 2018. [Google Scholar] [CrossRef] [PubMed]
  56. Zhou, H.; Huang, Z.; Chen, X.; Chen, S. miR-98 inhibits expression of TWIST to prevent progression of non-small cell lung cancers. Biomed. Pharmacother. 2017, 89, 1453–1461. [Google Scholar] [CrossRef] [PubMed]
  57. Liu, B.; Wu, X.; Liu, B.; Wang, C.; Liu, Y.; Zhou, Q.; Xu, K. MiR-26a enhances metastasis potential of lung cancer cells via AKT pathway by targeting PTEN. Biochim. Biophys. Acta 2012, 1822, 1692–1704. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Zeng, Y.; Zhu, J.; Shen, D.; Qin, H.; Lei, Z.; Li, W.; Huang, J.A.; Liu, Z. Repression of Smad4 by miR205 moderates TGF-beta-induced epithelial-mesenchymal transition in A549 cell lines. Int. J. Oncol. 2016, 49, 700–708. [Google Scholar] [CrossRef] [PubMed]
  59. Shi, Z.M.; Wang, L.; Shen, H.; Jiang, C.F.; Ge, X.; Li, D.M.; Wen, Y.Y.; Sun, H.R.; Pan, M.H.; Li, W.; et al. Downregulation of miR-218 contributes to epithelial-mesenchymal transition and tumor metastasis in lung cancer by targeting Slug/ZEB2 signaling. Oncogene 2017, 36, 2577–2588. [Google Scholar] [CrossRef] [PubMed]
  60. Li, Z.; Wang, X.; Li, W.; Wu, L.; Chang, L.; Chen, H. miRNA-124 modulates lung carcinoma cell migration and invasion. Int. J. Clin. Pharmacol. Ther. 2016, 54, 603–612. [Google Scholar] [CrossRef] [PubMed]
  61. Lin, X.; Yang, Z.; Zhang, P.; Liu, Y.; Shao, G. miR-154 inhibits migration and invasion of human non-small cell lung cancer by targeting ZEB2. Oncol. Lett. 2016, 12, 301–306. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Jin, X.; Yu, Y.; Zou, Q.; Wang, M.; Cui, Y.; Xie, J.; Wang, Z. MicroRNA-105 promotes epithelial-mesenchymal transition of nonsmall lung cancer cells through upregulating Mcl-1. J. Cell. Biochem. 2018. [Google Scholar] [CrossRef] [PubMed]
  63. Chen, Q.Y.; Jiao, D.M.; Wang, J.; Hu, H.; Tang, X.; Chen, J.; Mou, H.; Lu, W. miR-206 regulates cisplatin resistance and EMT in human lung adenocarcinoma cells partly by targeting MET. Oncotarget 2016, 7, 24510–24526. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Kim, M.; Jang, K.; Miller, P.; Picon-Ruiz, M.; Yeasky, T.M.; El-Ashry, D.; Slingerland, J.M. VEGFA links self-renewal and metastasis by inducing Sox2 to repress miR-452, driving Slug. Oncogene 2017, 36, 5199–5211. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Pan, H.L.; Wen, Z.S.; Huang, Y.C.; Cheng, X.; Wang, G.Z.; Zhou, Y.C.; Wang, Z.Y.; Guo, Y.Q.; Cao, Y.; Zhou, G.B. Down-regulation of microRNA-144 in air pollution-related lung cancer. Sci. Rep. 2015, 5, 14331. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Zhang, G.; An, H.; Fang, X. MicroRNA-144 regulates proliferation, invasion, and apoptosis of cells in malignant solitary pulmonary nodule via zinc finger E-box-binding homeobox 1. Int. J. Clin. Exp. Pathol. 2015, 8, 5960–5967. [Google Scholar] [PubMed]
  67. Lin, J.; Chen, Y.; Liu, L.; Shen, A.; Zheng, W. MicroRNA-155-5p suppresses the migration and invasion of lung adenocarcinoma A549 cells by targeting Smad2. Oncol. Lett. 2018, 16, 2444–2452. [Google Scholar] [CrossRef] [PubMed]
  68. Li, X.; Yu, Z.; Li, Y.; Liu, S.; Gao, C.; Hou, X.; Yao, R.; Cui, L. The tumor suppressor miR-124 inhibits cell proliferation by targeting STAT3 and functions as a prognostic marker for postoperative NSCLC patients. Int. J. Oncol. 2015, 46, 798–808. [Google Scholar] [CrossRef] [PubMed]
  69. Garofalo, M.; Di Leva, G.; Romano, G.; Nuovo, G.; Suh, S.S.; Ngankeu, A.; Taccioli, C.; Pichiorri, F.; Alder, H.; Secchiero, P.; et al. miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell 2009, 16, 498–509. [Google Scholar] [CrossRef] [PubMed]
  70. Jiao, A.; Sui, M.; Zhang, L.; Sun, P.; Geng, D.; Zhang, W.; Wang, X.; Li, J. MicroRNA-200c inhibits the metastasis of non-small cell lung cancer cells by targeting ZEB2, an epithelial-mesenchymal transition regulator. Mol. Med. Rep. 2016, 13, 3349–3355. [Google Scholar] [CrossRef] [PubMed]
  71. Xiao, B.; Liu, H.; Gu, Z.; Ji, C. Expression of microRNA-133 inhibits epithelial-mesenchymal transition in lung cancer cells by directly targeting FOXQ1. Arch. Bronconeumol. 2016, 52, 505–511. [Google Scholar] [CrossRef] [PubMed]
  72. Li, Q.; Ran, P.; Zhang, X.; Guo, X.; Yuan, Y.; Dong, T.; Zhu, B.; Zheng, S.; Xiao, C. Downregulation of N-Acetylglucosaminyltransferase GCNT3 by miR-302b-3p Decreases Non-Small Cell Lung Cancer (NSCLC) Cell Proliferation, Migration and Invasion. Cell. Physiol. Biochem. 2018, 50, 987–1004. [Google Scholar] [CrossRef] [PubMed]
  73. Tan, X.; Banerjee, P.; Liu, X.; Yu, J.; Gibbons, D.L.; Wu, P.; Scott, K.L.; Diao, L.; Zheng, X.; Wang, J.; et al. The epithelial-to-mesenchymal transition activator ZEB1 initiates a prometastatic competing endogenous RNA network. J. Clin. Investig. 2018, 128, 1267–1282. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Gregory, P.A.; Bert, A.G.; Paterson, E.L.; Barry, S.C.; Tsykin, A.; Farshid, G.; Vadas, M.A.; Khew-Goodall, Y.; Goodall, G.J. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol. 2008, 10, 593–601. [Google Scholar] [CrossRef] [PubMed]
  75. Lin, C.W.; Chang, Y.L.; Chang, Y.C.; Lin, J.C.; Chen, C.C.; Pan, S.H.; Wu, C.T.; Chen, H.Y.; Yang, S.C.; Hong, T.M.; et al. MicroRNA-135b promotes lung cancer metastasis by regulating multiple targets in the Hippo pathway and LZTS1. Nat. Commun. 2013, 4, 1877. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Chen, W.; Wang, J.; Liu, S.; Wang, S.; Cheng, Y.; Zhou, W.; Duan, C.; Zhang, C. MicroRNA-361-3p suppresses tumor cell proliferation and metastasis by directly targeting SH2B1 in NSCLC. J. Exp. Clin. Cancer Res. 2016, 35, 76. [Google Scholar] [CrossRef] [PubMed]
  77. Wang, J.; Zhou, F.; Yin, L.; Zhao, L.; Zhang, Y.; Wang, J. MicroRNA-199b targets the regulation of ZEB1 expression to inhibit cell proliferation, migration and invasion in nonsmall cell lung cancer. Mol. Med. Rep. 2017, 16, 5007–5014. [Google Scholar] [CrossRef] [PubMed]
  78. Duan, X.; Fu, Z.; Gao, L.; Zhou, J.; Deng, X.; Luo, X.; Fang, W.; Luo, R. Direct interaction between miR-203 and ZEB2 suppresses epithelial-mesenchymal transition signaling and reduces lung adenocarcinoma chemoresistance. Acta Biochim. Biophys. Sin. (Shanghai) 2016, 48, 1042–1049. [Google Scholar] [CrossRef] [PubMed]
  79. Yang, Y.; Liu, L.; Cai, J.; Wu, J.; Guan, H.; Zhu, X.; Yuan, J.; Chen, S.; Li, M. Targeting Smad2 and Smad3 by miR-136 suppresses metastasis-associated traits of lung adenocarcinoma cells. Oncol. Res. 2013, 21, 345–352. [Google Scholar] [CrossRef] [PubMed]
  80. Wang, J.; Wang, Y.; Sun, D.; Bu, J.; Ren, F.; Liu, B.; Zhang, S.; Xu, Z.; Pang, S.; Xu, S. miR-455-5p promotes cell growth and invasion by targeting SOCO3 in non-small cell lung cancer. Oncotarget 2017, 8, 114956–114965. [Google Scholar] [CrossRef] [PubMed]
  81. Burk, U.; Schubert, J.; Wellner, U.; Schmalhofer, O.; Vincan, E.; Spaderna, S.; Brabletz, T. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 2008, 9, 582–589. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Nishijima, N.; Seike, M.; Soeno, C.; Chiba, M.; Miyanaga, A.; Noro, R.; Sugano, T.; Matsumoto, M.; Kubota, K.; Gemma, A. miR-200/ZEB axis regulates sensitivity to nintedanib in non-small cell lung cancer cells. Int. J. Oncol. 2016, 48, 937–944. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Hou, Y.; Zhen, J.; Xu, X.; Zhen, K.; Zhu, B.; Pan, R.; Zhao, C. miR-215 functions as a tumor suppressor and directly targets ZEB2 in human non-small cell lung cancer. Oncol. Lett. 2015, 10, 1985–1992. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Mo, D.; Yang, D.; Xiao, X.; Sun, R.; Huang, L.; Xu, J. MiRNA-145 suppresses lung adenocarcinoma cell invasion and migration by targeting N-cadherin. Biotechnol. Lett. 2017, 39, 701–710. [Google Scholar] [CrossRef] [PubMed]
  85. Xie, Z.; Cai, L.; Li, R.; Zheng, J.; Wu, H.; Yang, X.; Li, H.; Wang, Z. Down-regulation of miR-489 contributes into NSCLC cell invasion through targeting SUZ12. Tumour Biol. 2015, 36, 6497–6505. [Google Scholar] [CrossRef] [PubMed]
  86. Yin, Q.; Han, Y.; Zhu, D.; Li, Z.; Shan, S.; Jin, W.; Lu, Q.; Ren, T. miR-145 and miR-497 suppress TGF-beta-induced epithelial-mesenchymal transition of non-small cell lung cancer by targeting MTDH. Cancer Cell Int. 2018, 18, 105. [Google Scholar] [CrossRef] [PubMed]
  87. Wang, R.T.; Xu, M.; Xu, C.X.; Song, Z.G.; Jin, H. Decreased expression of miR216a contributes to non-small-cell lung cancer progression. Clin. Cancer Res. 2014, 20, 4705–4716. [Google Scholar] [CrossRef] [PubMed]
  88. Hong-Yuan, W.; Xiao-Ping, C. miR-338-3p suppresses epithelial-mesenchymal transition and metastasis in human nonsmall cell lung cancer. Indian J. Cancer 2015, 52 (Suppl. 3), E168–E171. [Google Scholar] [CrossRef]
  89. Li, J.; Song, Y.; Wang, Y.; Luo, J.; Yu, W. MicroRNA-148a suppresses epithelial-to-mesenchymal transition by targeting ROCK1 in non-small cell lung cancer cells. Mol. Cell. Biochem. 2013, 380, 277–282. [Google Scholar] [CrossRef] [PubMed]
  90. Mo, X.; Zhang, F.; Liang, H.; Liu, M.; Li, H.; Xia, H. miR-544a promotes the invasion of lung cancer cells by targeting cadherina 1 in vitro. Onco-Targets Ther. 2014, 7, 895–900. [Google Scholar] [CrossRef] [PubMed]
  91. Li, Y.J.; Ping, C.; Tang, J.; Zhang, W. MicroRNA-455 suppresses non-small cell lung cancer through targeting ZEB1. Cell Biol. Int. 2016, 40, 621–628. [Google Scholar] [CrossRef] [PubMed]
  92. Tong, X.; Su, P.; Yang, H.; Chi, F.; Shen, L.; Feng, X.; Jiang, H.; Zhang, X.; Wang, Z. MicroRNA-598 inhibits the proliferation and invasion of non-small cell lung cancer cells by directly targeting ZEB2. Exp. Ther. Med. 2018, 16, 5417–5423. [Google Scholar] [CrossRef] [PubMed]
  93. Luo, H.; Liang, C. MicroRNA-148b inhibits proliferation and the epithelial-mesenchymal transition and increases radiosensitivity in non-small cell lung carcinomas by regulating ROCK1. Exp. Ther. Med. 2018, 15, 3609–3616. [Google Scholar] [CrossRef] [PubMed]
  94. Liu, Y.; Wang, F.; Xu, P. miR-590 accelerates lung adenocarcinoma migration and invasion through directly suppressing functional target OLFM4. Biomed. Pharmacother. 2017, 86, 466–474. [Google Scholar] [CrossRef] [PubMed]
  95. Diepenbruck, M.; Tiede, S.; Saxena, M.; Ivanek, R.; Kalathur, R.K.R.; Luond, F.; Meyer-Schaller, N.; Christofori, G. miR-1199-5p and Zeb1 function in a double-negative feedback loop potentially coordinating EMT and tumour metastasis. Nat. Commun. 2017, 8, 1168. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Li, H.; Ouyang, R.; Wang, Z.; Zhou, W.; Chen, H.; Jiang, Y.; Zhang, Y.; Li, H.; Liao, M.; Wang, W.; et al. MiR-150 promotes cellular metastasis in non-small cell lung cancer by targeting FOXO4. Sci. Rep. 2016, 6, 39001. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Wang, F.F.; Wang, S.; Xue, W.H.; Cheng, J.L. microRNA-590 suppresses the tumorigenesis and invasiveness of non-small cell lung cancer cells by targeting ADAM9. Mol. Cell. Biochem. 2016, 423, 29–37. [Google Scholar] [CrossRef] [PubMed]
  98. Xu, B.B.; Gu, Z.F.; Ma, M.; Wang, J.Y.; Wang, H.N. MicroRNA-590-5p suppresses the proliferation and invasion of non-small cell lung cancer by regulating GAB1. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 5954–5963. [Google Scholar] [CrossRef] [PubMed]
  99. Yang, C.L.; Zheng, X.L.; Ye, K.; Ge, H.; Sun, Y.N.; Lu, Y.F.; Fan, Q.X. MicroRNA-183 Acts as a Tumor Suppressor in Human Non-Small Cell Lung Cancer by Down-Regulating MTA1. Cell. Physiol. Biochem. 2018, 46, 93–106. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. Yang, F.; Wei, K.; Qin, Z.; Liu, W.; Shao, C.; Wang, C.; Ma, L.; Xie, M.; Shu, Y.; Shen, H. MiR-598 Suppresses Invasion and Migration by Negative Regulation of Derlin-1 and Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer. Cell. Physiol. Biochem. 2018, 47, 245–256. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  101. Xu, W.; Luo, F.; Sun, B.; Ye, H.; Li, J.; Shi, L.; Liu, Y.; Lu, X.; Wang, B.; Wang, Q.; et al. HIF-2alpha, acting via miR-191, is involved in angiogenesis and metastasis of arsenite-transformed HBE cells. Toxicol. Res. (Camb.) 2016, 5, 66–78. [Google Scholar] [CrossRef] [PubMed]
  102. Zhu, X.; Ju, S.; Yuan, F.; Chen, G.; Shu, Y.; Li, C.; Xu, Y.; Luo, J.; Xia, L. microRNA-664 enhances proliferation, migration and invasion of lung cancer cells. Exp. Ther. Med. 2017, 13, 3555–3562. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Yongchun, Z.; Linwei, T.; Xicai, W.; Lianhua, Y.; Guangqiang, Z.; Ming, Y.; Guanjian, L.; Yujie, L.; Yunchao, H. MicroRNA-195 inhibits non-small cell lung cancer cell proliferation, migration and invasion by targeting MYB. Cancer Lett. 2014, 347, 65–74. [Google Scholar] [CrossRef] [PubMed]
  104. Bao, L.; Lv, L.; Feng, J.; Chen, Y.; Wang, X.; Han, S.; Zhao, H. MiR-876-5p suppresses epithelial-mesenchymal transition of lung cancer by directly down-regulating bone morphogenetic protein 4. J. Biosci. 2017, 42, 671–681. [Google Scholar] [CrossRef] [PubMed]
  105. Liu, X.H.; Lu, K.H.; Wang, K.M.; Sun, M.; Zhang, E.B.; Yang, J.S.; Yin, D.D.; Liu, Z.L.; Zhou, J.; Liu, Z.J.; et al. MicroRNA-196a promotes non-small cell lung cancer cell proliferation and invasion through targeting HOXA5. BMC Cancer 2012, 12, 348. [Google Scholar] [CrossRef] [PubMed]
  106. Xu, L.; Xu, X.; Huang, H.; Ma, Z.; Zhang, S.; Niu, P.; Chen, Y.; Ping, J.; Lu, P.; Yu, C.; et al. MiR-1260b promotes the migration and invasion in non-small cell lung cancer via targeting PTPRK. Pathol. Res. Pract. 2018, 214, 776–783. [Google Scholar] [CrossRef] [PubMed]
  107. Krebs, A.M.; Mitschke, J.; Lasierra Losada, M.; Schmalhofer, O.; Boerries, M.; Busch, H.; Boettcher, M.; Mougiakakos, D.; Reichardt, W.; Bronsert, P.; et al. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat. Cell Biol. 2017, 19, 518–529. [Google Scholar] [CrossRef] [PubMed]
  108. Zhang, P.; Sun, Y.; Ma, L. ZEB1: At the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell Cycle 2015, 14, 481–487. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  109. Vandewalle, C.; Comijn, J.; De Craene, B.; Vermassen, P.; Bruyneel, E.; Andersen, H.; Tulchinsky, E.; Van Roy, F.; Berx, G. SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell-cell junctions. Nucleic Acids Res. 2005, 33, 6566–6578. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Larsen, J.E.; Nathan, V.; Osborne, J.K.; Farrow, R.K.; Deb, D.; Sullivan, J.P.; Dospoy, P.D.; Augustyn, A.; Hight, S.K.; Sato, M.; et al. ZEB1 drives epithelial-to-mesenchymal transition in lung cancer. J. Clin. Investig. 2016, 126, 3219–3235. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  111. Humphries, B.; Yang, C. The microRNA-200 family: Small molecules with novel roles in cancer development, progression and therapy. Oncotarget 2015, 6, 6472–6498. [Google Scholar] [CrossRef] [PubMed]
  112. Kolesnikoff, N.; Attema, J.L.; Roslan, S.; Bert, A.G.; Schwarz, Q.P.; Gregory, P.A.; Goodall, G.J. Specificity protein 1 (Sp1) maintains basal epithelial expression of the miR-200 family: Implications for epithelial-mesenchymal transition. J. Biol. Chem. 2014, 289, 11194–11205. [Google Scholar] [CrossRef] [PubMed]
  113. Kim, T.; Veronese, A.; Pichiorri, F.; Lee, T.J.; Jeon, Y.J.; Volinia, S.; Pineau, P.; Marchio, A.; Palatini, J.; Suh, S.S.; et al. p53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEB1 and ZEB2. J. Exp. Med. 2011, 208, 875–883. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Chang, C.J.; Chao, C.H.; Xia, W.; Yang, J.Y.; Xiong, Y.; Li, C.W.; Yu, W.H.; Rehman, S.K.; Hsu, J.L.; Lee, H.H.; et al. p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat. Cell Biol. 2011, 13, 317–323. [Google Scholar] [CrossRef] [PubMed]
  115. Li, J.; Tan, Q.; Yan, M.; Liu, L.; Lin, H.; Zhao, F.; Bao, G.; Kong, H.; Ge, C.; Zhang, F.; et al. miRNA-200c inhibits invasion and metastasis of human non-small cell lung cancer by directly targeting ubiquitin specific peptidase 25. Mol. Cancer 2014, 13, 166. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Hurteau, G.J.; Carlson, J.A.; Spivack, S.D.; Brock, G.J. Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. Cancer Res. 2007, 67, 7972–7976. [Google Scholar] [CrossRef] [PubMed]
  117. Mutlu, M.; Raza, U.; Saatci, O.; Eyupoglu, E.; Yurdusev, E.; Sahin, O. miR-200c: A versatile watchdog in cancer progression, EMT, and drug resistance. J. Mol. Med. (Berl.) 2016, 94, 629–644. [Google Scholar] [CrossRef] [PubMed]
  118. Hurteau, G.J.; Spivack, S.D.; Brock, G.J. Potential mRNA degradation targets of hsa-miR-200c, identified using informatics and qRT-PCR. Cell Cycle 2006, 5, 1951–1956. [Google Scholar] [CrossRef] [PubMed]
  119. Chen, L.; Gibbons, D.L.; Goswami, S.; Cortez, M.A.; Ahn, Y.H.; Byers, L.A.; Zhang, X.; Yi, X.; Dwyer, D.; Lin, W.; et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat. Commun. 2014, 5, 5241. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  120. Park, K.S.; Moon, Y.W.; Raffeld, M.; Lee, D.H.; Wang, Y.; Giaccone, G. High cripto-1 and low miR-205 expression levels as prognostic markers in early stage non-small cell lung cancer. Lung Cancer 2018, 116, 38–45. [Google Scholar] [CrossRef] [PubMed]
  121. Park, K.S.; Raffeld, M.; Moon, Y.W.; Xi, L.; Bianco, C.; Pham, T.; Lee, L.C.; Mitsudomi, T.; Yatabe, Y.; Okamoto, I.; et al. CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance. J. Clin. Investig. 2014, 124, 3003–3015. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Wellner, U.; Schubert, J.; Burk, U.C.; Schmalhofer, O.; Zhu, F.; Sonntag, A.; Waldvogel, B.; Vannier, C.; Darling, D.; zur Hausen, A.; et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat. Cell. Biol. 2009, 11, 1487–1495. [Google Scholar] [CrossRef] [PubMed]
  123. Bartel, D.P. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 2004, 116, 281–297. [Google Scholar] [CrossRef]
  124. Kaminska, B.; Wesolowska, A.; Danilkiewicz, M. TGF beta signalling and its role in tumour pathogenesis. Acta Biochim. Pol. 2005, 52, 329–337. [Google Scholar] [PubMed]
  125. Pain, M.; Bermudez, O.; Lacoste, P.; Royer, P.J.; Botturi, K.; Tissot, A.; Brouard, S.; Eickelberg, O.; Magnan, A. Tissue remodelling in chronic bronchial diseases: From the epithelial to mesenchymal phenotype. Eur. Respir. Rev. 2014, 23, 118–130. [Google Scholar] [CrossRef] [PubMed]
  126. Zaravinos, A. The Regulatory Role of MicroRNAs in EMT and Cancer. J. Oncol. 2015, 2015, 865816. [Google Scholar] [CrossRef] [PubMed]
  127. Zhang, H.J.; Wang, H.Y.; Zhang, H.T.; Su, J.M.; Zhu, J.; Wang, H.B.; Zhou, W.Y.; Zhang, H.; Zhao, M.C.; Zhang, L.; et al. Transforming growth factor-beta1 promotes lung adenocarcinoma invasion and metastasis by epithelial-to-mesenchymal transition. Mol. Cell. Biochem. 2011, 355, 309–314. [Google Scholar] [CrossRef] [PubMed]
  128. Hasegawa, Y.; Takanashi, S.; Kanehira, Y.; Tsushima, T.; Imai, T.; Okumura, K. Transforming growth factor-beta1 level correlates with angiogenesis, tumor progression, and prognosis in patients with nonsmall cell lung carcinoma. Cancer 2001, 91, 964–971. [Google Scholar] [CrossRef]
  129. Jakubowska, K.; Naumnik, W.; Niklinska, W.; Chyczewska, E. Clinical Significance of HMGB-1 and TGF-beta Level in Serum and BALF of Advanced Non-Small Cell Lung Cancer. Adv. Exp. Med. Biol. 2015, 852, 49–58. [Google Scholar] [CrossRef] [PubMed]
  130. Soucheray, M.; Capelletti, M.; Pulido, I.; Kuang, Y.; Paweletz, C.P.; Becker, J.H.; Kikuchi, E.; Xu, C.; Patel, T.B.; Al-Shahrour, F.; et al. Intratumoral Heterogeneity in EGFR-Mutant NSCLC Results in Divergent Resistance Mechanisms in Response to EGFR Tyrosine Kinase Inhibition. Cancer Res. 2015, 75, 4372–4383. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  131. Sequist, L.V.; Waltman, B.A.; Dias-Santagata, D.; Digumarthy, S.; Turke, A.B.; Fidias, P.; Bergethon, K.; Shaw, A.T.; Gettinger, S.; Cosper, A.K.; et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 2011, 3, 75ra26. [Google Scholar] [CrossRef] [PubMed]
  132. Kong, W.; Yang, H.; He, L.; Zhao, J.J.; Coppola, D.; Dalton, W.S.; Cheng, J.Q. MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA. Mol. Cell. Biol. 2008, 28, 6773–6784. [Google Scholar] [CrossRef] [PubMed]
  133. Santibanez, J.F.; Obradovic, H.; Kukolj, T.; Krstic, J. Transforming growth factor-beta, matrix metalloproteinases, and urokinase-type plasminogen activator interaction in the cancer epithelial to mesenchymal transition. Dev. Dyn. 2018, 247, 382–395. [Google Scholar] [CrossRef] [PubMed]
  134. Yao, Y.; Shen, H.; Zhou, Y.; Yang, Z.; Hu, T. MicroRNA-215 suppresses the proliferation, migration and invasion of non-small cell lung carcinoma cells through the downregulation of matrix metalloproteinase-16 expression. Exp. Ther. Med. 2018, 15, 3239–3246. [Google Scholar] [CrossRef] [PubMed]
  135. Li, T.T.; Gao, X.; Gao, L.; Gan, B.L.; Xie, Z.C.; Zeng, J.J.; Chen, G. Role of upregulated miR-136-5p in lung adenocarcinoma: A study of 1242 samples utilizing bioinformatics analysis. Pathol. Res. Pract. 2018, 214, 750–766. [Google Scholar] [CrossRef] [PubMed]
  136. Jin, G.; Kim, M.J.; Jeon, H.S.; Choi, J.E.; Kim, D.S.; Lee, E.B.; Cha, S.I.; Yoon, G.S.; Kim, C.H.; Jung, T.H.; et al. PTEN mutations and relationship to EGFR, ERBB2, KRAS, and TP53 mutations in non-small cell lung cancers. Lung Cancer 2010, 69, 279–283. [Google Scholar] [CrossRef] [PubMed]
  137. Kohno, T.; Takahashi, M.; Manda, R.; Yokota, J. Inactivation of the PTEN/MMAC1/TEP1 gene in human lung cancers. Genes Chromosomes Cancer 1998, 22, 152–156. [Google Scholar] [CrossRef]
  138. Yu, Y.X.; Wang, Y.; Liu, H. Overexpression of PTEN suppresses non-small-cell lung carcinoma metastasis through inhibition of integrin alphaVbeta6 signaling. Am. J. Transl. Res. 2017, 9, 3304–3314. [Google Scholar] [PubMed]
  139. Xiao, J.; Hu, C.P.; He, B.X.; Chen, X.; Lu, X.X.; Xie, M.X.; Li, W.; He, S.Y.; You, S.J.; Chen, Q. PTEN expression is a prognostic marker for patients with non-small cell lung cancer: A systematic review and meta-analysis of the literature. Oncotarget 2016, 7, 57832–57840. [Google Scholar] [CrossRef] [PubMed]
  140. Liu, C.; Shi, X.; Wang, L.; Wu, Y.; Jin, F.; Bai, C.; Song, Y. SUZ12 is involved in progression of non-small cell lung cancer by promoting cell proliferation and metastasis. Tumour Biol. 2014, 35, 6073–6082. [Google Scholar] [CrossRef] [PubMed]
  141. Liu, T.; Zhang, S.; Chen, J.; Jiang, K.; Zhang, Q.; Guo, K.; Liu, Y. The transcriptional profiling of glycogenes associated with hepatocellular carcinoma metastasis. PLoS ONE 2014, 9, e107941. [Google Scholar] [CrossRef] [PubMed]
  142. Huang, M.C.; Chen, H.Y.; Huang, H.C.; Huang, J.; Liang, J.T.; Shen, T.L.; Lin, N.Y.; Ho, C.C.; Cho, I.M.; Hsu, S.M. C2GnT-M is downregulated in colorectal cancer and its re-expression causes growth inhibition of colon cancer cells. Oncogene 2006, 25, 3267–3276. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Yu, S.L.; Chen, H.Y.; Chang, G.C.; Chen, C.Y.; Chen, H.W.; Singh, S.; Cheng, C.L.; Yu, C.J.; Lee, Y.C.; Chen, H.S.; et al. MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell 2008, 13, 48–57. [Google Scholar] [CrossRef] [PubMed]
  144. Aiso, T.; Ohtsuka, K.; Ueda, M.; Karita, S.; Yokoyama, T.; Takata, S.; Matsuki, N.; Kondo, H.; Takizawa, H.; Okada, A.A.; et al. Serum levels of candidate microRNA diagnostic markers differ among the stages of non-small-cell lung cancer. Oncol. Lett. 2018, 16, 6643–6651. [Google Scholar] [CrossRef] [PubMed]
  145. Pastorkova, Z.; Skarda, J.; Andel, J. The role of microRNA in metastatic processes of non-small cell lung carcinoma. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech. Repub. 2016, 160, 343–357. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  146. Roodman, G.D. Mechanisms of bone metastasis. N. Engl. J. Med. 2004, 350, 1655–1664. [Google Scholar] [CrossRef] [PubMed]
  147. Mundy, G.R. Metastasis to bone: Causes, consequences and therapeutic opportunities. Nat. Rev. Cancer 2002, 2, 584–593. [Google Scholar] [CrossRef] [PubMed]
  148. Xie, L.; Yang, Z.; Li, G.; Shen, L.; Xiang, X.; Liu, X.; Xu, D.; Xu, L.; Chen, Y.; Tian, Z.; et al. Genome-wide identification of bone metastasis-related microRNAs in lung adenocarcinoma by high-throughput sequencing. PLoS ONE 2013, 8, e61212. [Google Scholar] [CrossRef] [PubMed]
  149. Guo, Q.; Zhang, H.; Zhang, L.; He, Y.; Weng, S.; Dong, Z.; Wang, J.; Zhang, P.; Nao, R. MicroRNA-21 regulates non-small cell lung cancer cell proliferation by affecting cell apoptosis via COX-19. Int. J. Clin. Exp. Med. 2015, 8, 8835–8841. [Google Scholar] [PubMed]
  150. Srinivasan, S.; Avadhani, N.G. Cytochrome c oxidase dysfunction in oxidative stress. Free Radic. Biol. Med. 2012, 53, 1252–1263. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  151. Zou, H.; Li, Y.; Liu, X.; Wang, X. An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J. Biol. Chem. 1999, 274, 11549–11556. [Google Scholar] [CrossRef] [PubMed]
  152. Xu, Z.; Liu, X.; Wang, H.; Li, J.; Dai, L.; Li, J.; Dong, C. Lung adenocarcinoma cell-derived exosomal miR-21 facilitates osteoclastogenesis. Gene 2018, 666, 116–122. [Google Scholar] [CrossRef] [PubMed]
  153. Cai, L.; Ye, Y.; Jiang, Q.; Chen, Y.; Lyu, X.; Li, J.; Wang, S.; Liu, T.; Cai, H.; Yao, K.; et al. Epstein-Barr virus-encoded microRNA BART1 induces tumour metastasis by regulating PTEN-dependent pathways in nasopharyngeal carcinoma. Nat. Commun. 2015, 6, 7353. [Google Scholar] [CrossRef] [PubMed]
  154. Tang, S.; Bertke, A.S.; Patel, A.; Wang, K.; Cohen, J.I.; Krause, P.R. An acutely and latently expressed herpes simplex virus 2 viral microRNA inhibits expression of ICP34.5, a viral neurovirulence factor. Proc. Natl. Acad. Sci. USA 2008, 105, 10931–10936. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. Wang, X.; Liu, S.; Zhou, Z.; Yan, H.; Xiao, J. A herpes simplex virus type 2-encoded microRNA promotes tumor cell metastasis by targeting suppressor of cytokine signaling 2 in lung cancer. Tumour Biol. 2017, 39. [Google Scholar] [CrossRef] [PubMed]
  156. Sen, B.; Peng, S.; Woods, D.M.; Wistuba, I.; Bell, D.; El-Naggar, A.K.; Lai, S.Y.; Johnson, F.M. STAT5A-mediated SOCS2 expression regulates Jak2 and STAT3 activity following c-Src inhibition in head and neck squamous carcinoma. Clin. Cancer Res. 2012, 18, 127–139. [Google Scholar] [CrossRef] [PubMed]
  157. Wikman, H.; Kettunen, E.; Seppanen, J.K.; Karjalainen, A.; Hollmen, J.; Anttila, S.; Knuutila, S. Identification of differentially expressed genes in pulmonary adenocarcinoma by using cDNA array. Oncogene 2002, 21, 5804–5813. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  158. Kuo, P.L.; Liao, S.H.; Hung, J.Y.; Huang, M.S.; Hsu, Y.L. MicroRNA-33a functions as a bone metastasis suppressor in lung cancer by targeting parathyroid hormone related protein. Biochim. Biophys. Acta 2013, 1830, 3756–3766. [Google Scholar] [CrossRef] [PubMed]
  159. Xu, S.; Yang, F.; Liu, R.; Li, X.; Fan, H.; Liu, J.; Wei, S.; Chen, G.; Chen, J.; Da, Y. Serum microRNA-139-5p is downregulated in lung cancer patients with lytic bone metastasis. Oncol. Rep. 2018, 39, 2376–2384. [Google Scholar] [CrossRef] [PubMed]
  160. Valencia, K.; Luis-Ravelo, D.; Bovy, N.; Anton, I.; Martinez-Canarias, S.; Zandueta, C.; Ormazabal, C.; Struman, I.; Tabruyn, S.; Rebmann, V.; et al. miRNA cargo within exosome-like vesicle transfer influences metastatic bone colonization. Mol. Oncol. 2014, 8, 689–703. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  161. Wei, Y.; Li, D.; Wang, D.; Qiu, T.; Liu, K. Evaluation of microRNA-203 in bone metastasis of patients with non-small cell lung cancer through TGF-beta/SMAD2 expression. Oncol. Rep. 2017. [Google Scholar] [CrossRef] [PubMed]
  162. Grinberg-Rashi, H.; Ofek, E.; Perelman, M.; Skarda, J.; Yaron, P.; Hajduch, M.; Jacob-Hirsch, J.; Amariglio, N.; Krupsky, M.; Simansky, D.A.; et al. The expression of three genes in primary non-small cell lung cancer is associated with metastatic spread to the brain. Clin. Cancer Res. 2009, 15, 1755–1761. [Google Scholar] [CrossRef] [PubMed]
  163. Zhao, C.; Xu, Y.; Zhang, Y.; Tan, W.; Xue, J.; Yang, Z.; Zhang, Y.; Lu, Y.; Hu, X. Downregulation of miR-145 contributes to lung adenocarcinoma cell growth to form brain metastases. Oncol. Rep. 2013, 30, 2027–2034. [Google Scholar] [CrossRef] [PubMed]
  164. Lu, Y.; Govindan, R.; Wang, L.; Liu, P.Y.; Goodgame, B.; Wen, W.; Sezhiyan, A.; Pfeifer, J.; Li, Y.F.; Hua, X.; et al. MicroRNA profiling and prediction of recurrence/relapse-free survival in stage I lung cancer. Carcinogenesis 2012, 33, 1046–1054. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  165. Donzelli, S.; Mori, F.; Bellissimo, T.; Sacconi, A.; Casini, B.; Frixa, T.; Roscilli, G.; Aurisicchio, L.; Facciolo, F.; Pompili, A.; et al. Epigenetic silencing of miR-145-5p contributes to brain metastasis. Oncotarget 2015, 6, 35183–35201. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  166. Singh, M.; Garg, N.; Venugopal, C.; Hallett, R.; Tokar, T.; McFarlane, N.; Mahendram, S.; Bakhshinyan, D.; Manoranjan, B.; Vora, P.; et al. STAT3 pathway regulates lung-derived brain metastasis initiating cell capacity through miR-21 activation. Oncotarget 2015, 6, 27461–27477. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  167. Hwang, S.J.; Lee, H.W.; Kim, H.R.; Song, H.J.; Lee, D.H.; Lee, H.; Shin, C.H.; Joung, J.G.; Kim, D.H.; Joo, K.M.; et al. Overexpression of microRNA-95-3p suppresses brain metastasis of lung adenocarcinoma through downregulation of cyclin D1. Oncotarget 2015, 6, 20434–20448. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  168. Berrout, J.; Kyriakopoulou, E.; Moparthi, L.; Hogea, A.S.; Berrout, L.; Ivan, C.; Lorger, M.; Boyle, J.; Peers, C.; Muench, S.; et al. TRPA1-FGFR2 binding event is a regulatory oncogenic driver modulated by miRNA-142-3p. Nat. Commun. 2017, 8, 947. [Google Scholar] [CrossRef] [PubMed]
  169. Remon, J.; Alvarez-Berdugo, D.; Majem, M.; Moran, T.; Reguart, N.; Lianes, P. miRNA-197 and miRNA-184 are associated with brain metastasis in EGFR-mutant lung cancers. Clin. Transl. Oncol. 2016, 18, 153–159. [Google Scholar] [CrossRef] [PubMed]
  170. Zhao, S.; Yu, J.; Wang, L. Machine Learning Based Prediction of Brain Metastasis of Patients with IIIA-N2 Lung Adenocarcinoma by a Three-miRNA Signature. Transl. Oncol. 2018, 11, 157–167. [Google Scholar] [CrossRef] [PubMed]
  171. Arora, S.; Ranade, A.R.; Tran, N.L.; Nasser, S.; Sridhar, S.; Korn, R.L.; Ross, J.T.; Dhruv, H.; Foss, K.M.; Sibenaller, Z.; et al. MicroRNA-328 is associated with (non-small) cell lung cancer (NSCLC) brain metastasis and mediates NSCLC migration. Int. J. Cancer 2011, 129, 2621–2631. [Google Scholar] [CrossRef] [PubMed]
  172. Wei, C.H.; Wu, G.; Cai, Q.; Gao, X.C.; Tong, F.; Zhou, R.; Zhang, R.G.; Dong, J.H.; Hu, Y.; Dong, X.R. MicroRNA-330-3p promotes cell invasion and metastasis in non-small cell lung cancer through GRIA3 by activating MAPK/ERK signaling pathway. J. Hematol. Oncol. 2017, 10, 125. [Google Scholar] [CrossRef] [PubMed]
  173. Jiang, L.P.; Zhu, Z.T.; Zhang, Y.; He, C.Y. Downregulation of MicroRNA-330 Correlates with the Radiation Sensitivity and Prognosis of Patients with Brain Metastasis from Lung Cancer. Cell. Physiol. Biochem. 2017, 42, 2220–2229. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  174. Chen, L.J.; Li, X.Y.; Zhao, Y.Q.; Liu, W.J.; Wu, H.J.; Liu, J.; Mu, X.Q.; Wu, H.B. Down-regulated microRNA-375 expression as a predictive biomarker in non-small cell lung cancer brain metastasis and its prognostic significance. Pathol. Res. Pract. 2017, 213, 882–888. [Google Scholar] [CrossRef] [PubMed]
  175. Chen, L.T.; Xu, S.D.; Xu, H.; Zhang, J.F.; Ning, J.F.; Wang, S.F. MicroRNA-378 is associated with non-small cell lung cancer brain metastasis by promoting cell migration, invasion and tumor angiogenesis. Med. Oncol. 2012, 29, 1673–1680. [Google Scholar] [CrossRef] [PubMed]
  176. Sun, G.; Ding, X.; Bi, N.; Wu, L.; Wang, J.; Zhang, W.; Dong, X.; Lv, N.; Song, Y.; Zhan, Q.; et al. MiR-423-5p in brain metastasis: Potential role in diagnostics and molecular biology. Cell Death Dis. 2018, 9, 936. [Google Scholar] [CrossRef] [PubMed]
  177. Li, J.; Feng, Q.; Wei, X.; Yu, Y. MicroRNA-490 regulates lung cancer metastasis by targeting poly r(C)-binding protein 1. Tumour Biol. 2016, 37, 15221–15228. [Google Scholar] [CrossRef] [PubMed]
  178. He, X.; Chen, S.Y.; Yang, Z.; Zhang, J.; Wang, W.; Liu, M.Y.; Niu, Y.; Wei, X.M.; Li, H.M.; Hu, W.N.; et al. miR-4317 suppresses non-small cell lung cancer (NSCLC) by targeting fibroblast growth factor 9 (FGF9) and cyclin D2 (CCND2). J. Exp. Clin. Cancer Res. 2018, 37, 230. [Google Scholar] [CrossRef] [PubMed]
  179. Loffler, D.; Brocke-Heidrich, K.; Pfeifer, G.; Stocsits, C.; Hackermuller, J.; Kretzschmar, A.K.; Burger, R.; Gramatzki, M.; Blumert, C.; Bauer, K.; et al. Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer. Blood 2007, 110, 1330–1333. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  180. Iliopoulos, D.; Jaeger, S.A.; Hirsch, H.A.; Bulyk, M.L.; Struhl, K. STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol. Cell 2010, 39, 493–506. [Google Scholar] [CrossRef] [PubMed]
  181. De Oliveira, J.C.; Scrideli, C.A.; Brassesco, M.S.; Morales, A.G.; Pezuk, J.A.; Queiroz Rde, P.; Yunes, J.A.; Brandalise, S.R.; Tone, L.G. Differential miRNA expression in childhood acute lymphoblastic leukemia and association with clinical and biological features. Leuk. Res. 2012, 36, 293–298. [Google Scholar] [CrossRef] [PubMed]
  182. Subra, C.; Grand, D.; Laulagnier, K.; Stella, A.; Lambeau, G.; Paillasse, M.; De Medina, P.; Monsarrat, B.; Perret, B.; Silvente-Poirot, S.; et al. Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins. J. Lipid Res. 2010, 51, 2105–2120. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  183. Bang, C.; Thum, T. Exosomes: New players in cell-cell communication. Int. J. Biochem. Cell Biol. 2012, 44, 2060–2064. [Google Scholar] [CrossRef] [PubMed]
  184. Wittmann, J.; Jack, H.M. Serum microRNAs as powerful cancer biomarkers. Biochim. Biophys. Acta 2010, 1806, 200–207. [Google Scholar] [CrossRef] [PubMed]
  185. Peinado, H.; Aleckovic, M.; Lavotshkin, S.; Matei, I.; Costa-Silva, B.; Moreno-Bueno, G.; Hergueta-Redondo, M.; Williams, C.; Garcia-Santos, G.; Ghajar, C.; et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 2012, 18, 883–891. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  186. Rana, S.; Malinowska, K.; Zoller, M. Exosomal tumor microRNA modulates premetastatic organ cells. Neoplasia 2013, 15, 281–295. [Google Scholar] [CrossRef] [PubMed]
  187. Carr, I. Lymphatic metastasis. Cancer Metastasis Rev. 1983, 2, 307–317. [Google Scholar] [CrossRef] [PubMed]
  188. Eisenhauer, E.A.; Therasse, P.; Bogaerts, J.; Schwartz, L.H.; Sargent, D.; Ford, R.; Dancey, J.; Arbuck, S.; Gwyther, S.; Mooney, M.; et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur. J. Cancer 2009, 45, 228–247. [Google Scholar] [CrossRef] [PubMed]
  189. Asamura, H.; Suzuki, K.; Kondo, H.; Tsuchiya, R. Where is the boundary between N1 and N2 stations in lung cancer? Ann. Thorac. Surg. 2000, 70, 1839–1845; discussion 1845–1836. [Google Scholar] [CrossRef]
  190. Wu, J.; Ohta, Y.; Minato, H.; Tsunezuka, Y.; Oda, M.; Watanabe, Y.; Watanabe, G. Nodal occult metastasis in patients with peripheral lung adenocarcinoma of 2.0 cm or less in diameter. Ann. Thorac. Surg. 2001, 71, 1772–1777; discussion 1777–1778. [Google Scholar] [CrossRef]
  191. Ong, P.; Grosu, H.; Eapen, G.A.; Rodriguez, M.; Lazarus, D.; Ost, D.; Jimenez, C.A.; Morice, R.; Bandi, V.; Tamara, L.; et al. Endobronchial ultrasound-guided transbronchial needle aspiration for systematic nodal staging of lung cancer in patients with N0 disease by computed tomography and integrated positron emission tomography-computed tomography. Ann. Am. Thorac. Soc. 2015, 12, 415–419. [Google Scholar] [CrossRef] [PubMed]
  192. Park, S.Y.; Yoon, J.K.; Park, K.J.; Lee, S.J. Prediction of occult lymph node metastasis using volume-based PET parameters in small-sized peripheral non-small cell lung cancer. Cancer Imaging 2015, 15, 21. [Google Scholar] [CrossRef] [PubMed]
  193. Pieterman, R.M.; van Putten, J.W.; Meuzelaar, J.J.; Mooyaart, E.L.; Vaalburg, W.; Koeter, G.H.; Fidler, V.; Pruim, J.; Groen, H.J. Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N. Engl. J. Med. 2000, 343, 254–261. [Google Scholar] [CrossRef] [PubMed]
  194. Capodanno, A.; Boldrini, L.; Proietti, A.; Ali, G.; Pelliccioni, S.; Niccoli, C.; D’Incecco, A.; Cappuzzo, F.; Chella, A.; Lucchi, M.; et al. Let-7g and miR-21 expression in non-small cell lung cancer: Correlation with clinicopathological and molecular features. Int. J. Oncol. 2013, 43, 765–774. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  195. Zhao, Q.; Zhang, B.; Shao, Y.; Chen, L.; Wang, X.; Zhang, Z.; Shu, Y.; Guo, R. Correlation between the expression levels of miR-1 and PIK3CA in non-small-cell lung cancer and their relationship with clinical characteristics and prognosis. Future Oncol. 2014, 10, 49–57. [Google Scholar] [CrossRef] [PubMed]
  196. Zhang, X.; Yang, D.; Wei, Y. Overexpressed CDR1as functions as an oncogene to promote the tumor progression via miR-7 in non-small-cell lung cancer. Onco-Targets Ther. 2018, 11, 3979–3987. [Google Scholar] [CrossRef] [PubMed]
  197. Cheng, M.W.; Shen, Z.T.; Hu, G.Y.; Luo, L.G. Prognostic Significance of microRNA-7 and its Roles in the Regulation of Cisplatin Resistance in Lung Adenocarcinoma. Cell. Physiol. Biochem. 2017, 42, 660–672. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  198. Muraoka, T.; Soh, J.; Toyooka, S.; Maki, Y.; Shien, K.; Furukawa, M.; Ueno, T.; Tanaka, N.; Yamamoto, H.; Asano, H.; et al. Impact of aberrant methylation of microRNA-9 family members on non-small cell lung cancers. Mol. Clin. Oncol. 2013, 1, 185–189. [Google Scholar] [CrossRef] [PubMed]
  199. Xu, T.; Liu, X.; Han, L.; Shen, H.; Liu, L.; Shu, Y. Up-regulation of miR-9 expression as a poor prognostic biomarker in patients with non-small cell lung cancer. Clin. Transl. Oncol. 2014, 16, 469–475. [Google Scholar] [CrossRef] [PubMed]
  200. Yu, T.; Liu, L.; Li, J.; Yan, M.; Lin, H.; Liu, Y.; Chu, D.; Tu, H.; Gu, A.; Yao, M. MiRNA-10a is upregulated in NSCLC and may promote cancer by targeting PTEN. Oncotarget 2015, 6, 30239–30250. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  201. Zhang, J.; Xu, L.; Yang, Z.; Lu, H.; Hu, D.; Li, W.; Zhang, Z.; Liu, B.; Ma, S. MicroRNA-10b indicates a poor prognosis of non-small cell lung cancer and targets E-cadherin. Clin. Transl. Oncol. 2015, 17, 209–214. [Google Scholar] [CrossRef] [PubMed]
  202. Yang, Y.L.; Xu, L.P.; Zhuo, F.L.; Wang, T.Y. Prognostic value of microRNA-10b overexpression in peripheral blood mononuclear cells of nonsmall-cell lung cancer patients. Tumour Biol. 2015, 36, 7069–7075. [Google Scholar] [CrossRef] [PubMed]
  203. Yang, Y.L.; Wang, W.; Xu, L.P. Predictive value of microRNA-10b expression in peripheral blood mononuclear cells in evaluating short- and long-term efficacy of chemotherapy for patients with advanced non-small-cell lung cancer. Neoplasma 2018, 65, 610–619. [Google Scholar] [CrossRef] [PubMed]
  204. Li, Y.; Li, Y.; Liu, J.; Fan, Y.; Li, X.; Dong, M.; Liu, H.; Chen, J. Expression levels of microRNA-145 and microRNA-10b are associated with metastasis in non-small cell lung cancer. Cancer Biol. Ther. 2016, 17, 272–279. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  205. Zhang, G.; An, X.; Zhao, H.; Zhang, Q.; Zhao, H. Long non-coding RNA HNF1A-AS1 promotes cell proliferation and invasion via regulating miR-17-5p in non-small cell lung cancer. Biomed. Pharmacother. 2018, 98, 594–599. [Google Scholar] [CrossRef] [PubMed]
  206. Shen, Z.; Wu, X.; Wang, Z.; Li, B.; Zhu, X. Effect of miR-18a overexpression on the radiosensitivity of non-small cell lung cancer. Int. J. Clin. Exp. Pathol. 2015, 8, 643–648. [Google Scholar] [PubMed]
  207. Lin, Q.; Chen, T.; Lin, Q.; Lin, G.; Lin, J.; Chen, G.; Guo, L. Serum miR-19a expression correlates with worse prognosis of patients with non-small cell lung cancer. J. Surg. Oncol. 2013, 107, 767–771. [Google Scholar] [CrossRef] [PubMed]
  208. Wu, C.; Cao, Y.; He, Z.; He, J.; Hu, C.; Duan, H.; Jiang, J. Serum levels of miR-19b and miR-146a as prognostic biomarkers for non-small cell lung cancer. Tohoku J. Exp. Med. 2014, 232, 85–95. [Google Scholar] [CrossRef] [PubMed]
  209. Liu, X.G.; Zhu, W.Y.; Huang, Y.Y.; Ma, L.N.; Zhou, S.Q.; Wang, Y.K.; Zeng, F.; Zhou, J.H.; Zhang, Y.K. High expression of serum miR-21 and tumor miR-200c associated with poor prognosis in patients with lung cancer. Med. Oncol. 2012, 29, 618–626. [Google Scholar] [CrossRef] [PubMed]
  210. Wang, Z.X.; Bian, H.B.; Wang, J.R.; Cheng, Z.X.; Wang, K.M.; De, W. Prognostic significance of serum miRNA-21 expression in human non-small cell lung cancer. J. Surg. Oncol. 2011, 104, 847–851. [Google Scholar] [CrossRef] [PubMed]
  211. Liu, Z.L.; Wang, H.; Liu, J.; Wang, Z.X. MicroRNA-21 (miR-21) expression promotes growth, metastasis, and chemo- or radioresistance in non-small cell lung cancer cells by targeting PTEN. Mol. Cell. Biochem. 2013, 372, 35–45. [Google Scholar] [CrossRef] [PubMed]
  212. Wang, X.C.; Wang, W.; Zhang, Z.B.; Zhao, J.; Tan, X.G.; Luo, J.C. Overexpression of miRNA-21 promotes radiation-resistance of non-small cell lung cancer. Radiat. Oncol. 2013, 8, 146. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  213. Tian, L.; Shan, W.; Zhang, Y.; Lv, X.; Li, X.; Wei, C. Up-Regulation of miR-21 Expression Predicate Advanced Clinicopathological Features and Poor Prognosis in Patients with Non-Small Cell Lung Cancer. Pathol. Oncol. Res. 2016, 22, 161–167. [Google Scholar] [CrossRef] [PubMed]
  214. Xu, F.X.; Su, Y.L.; Zhang, H.; Kong, J.Y.; Yu, H.; Qian, B.Y. Prognostic implications for high expression of MiR-25 in lung adenocarcinomas of female non-smokers. Asian Pac. J. Cancer Prev. 2014, 15, 1197–1203. [Google Scholar] [CrossRef] [PubMed]
  215. Wang, H.Y.; Tu, Y.S.; Long, J.; Zhang, H.Q.; Qi, C.L.; Xie, X.B.; Li, S.H.; Zhang, Y.J. SRF-miR29b-MMP2 axis inhibits NSCLC invasion and metastasis. Int. J. Oncol. 2015, 47, 641–649. [Google Scholar] [CrossRef] [PubMed]
  216. Jiang, B.Y.; Zhang, X.C.; Su, J.; Meng, W.; Yang, X.N.; Yang, J.J.; Zhou, Q.; Chen, Z.Y.; Chen, Z.H.; Xie, Z.; et al. BCL11A overexpression predicts survival and relapse in non-small cell lung cancer and is modulated by microRNA-30a and gene amplification. Mol. Cancer 2013, 12, 61. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  217. Qi, Z.; Zhang, B.; Zhang, J.; Hu, Q.; Xu, F.; Chen, B.; Zhu, C. MicroRNA-30b inhibits non-small cell lung cancer cell growth by targeting the epidermal growth factor receptor. Neoplasma 2018, 65, 192–200. [Google Scholar] [CrossRef] [PubMed]
  218. Chen, S.; Li, P.; Yang, R.; Cheng, R.; Zhang, F.; Wang, Y.; Chen, X.; Sun, Q.; Zang, W.; Du, Y.; et al. microRNA-30b inhibits cell invasion and migration through targeting collagen triple helix repeat containing 1 in non-small cell lung cancer. Cancer Cell Int. 2015, 15, 85. [Google Scholar] [CrossRef] [PubMed]
  219. Meng, W.; Ye, Z.; Cui, R.; Perry, J.; Dedousi-Huebner, V.; Huebner, A.; Wang, Y.; Li, B.; Volinia, S.; Nakanishi, H.; et al. MicroRNA-31 predicts the presence of lymph node metastases and survival in patients with lung adenocarcinoma. Clin. Cancer Res. 2013, 19, 5423–5433. [Google Scholar] [CrossRef] [PubMed]
  220. Bai, Y.; Wang, Y.L.; Yao, W.J.; Guo, L.; Xi, H.F.; Li, S.Y.; Zhao, B.S. Expression of miR-32 in human non-small cell lung cancer and its correlation with tumor progression and patient survival. Int. J. Clin. Exp. Pathol. 2015, 8, 824–829. [Google Scholar] [PubMed]
  221. Zhao, K.; Cheng, J.; Chen, B.; Liu, Q.; Xu, D.; Zhang, Y. Circulating microRNA-34 family low expression correlates with poor prognosis in patients with non-small cell lung cancer. J. Thorac. Dis. 2017, 9, 3735–3746. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  222. Ren, P.; Gong, F.; Zhang, Y.; Jiang, J.; Zhang, H. MicroRNA-92a promotes growth, metastasis, and chemoresistance in non-small cell lung cancer cells by targeting PTEN. Tumour Biol. 2016, 37, 3215–3225. [Google Scholar] [CrossRef] [PubMed]
  223. Li, J.; Li, P.; Chen, T.; Gao, G.; Chen, X.; Du, Y.; Zhang, R.; Yang, R.; Zhao, W.; Dun, S.; et al. Expression of microRNA-96 and its potential functions by targeting FOXO3 in non-small cell lung cancer. Tumour Biol. 2015, 36, 685–692. [Google Scholar] [CrossRef] [PubMed]
  224. Wang, K.; Dong, L.; Fang, Q.; Xia, H.; Hou, X. Low serum miR-98 as an unfavorable prognostic biomarker in patients with non-small cell lung cancer. Cancer Biomark. 2017, 20, 283–288. [Google Scholar] [CrossRef] [PubMed]
  225. Gu, W.; Fang, S.; Gao, L.; Tan, Y.; Yang, Z. Clinic significance of microRNA-99a expression in human lung adenocarcinoma. J. Surg. Oncol. 2013, 108, 248–255. [Google Scholar] [CrossRef] [PubMed]
  226. Liu, J.; Lu, K.H.; Liu, Z.L.; Sun, M.; De, W.; Wang, Z.X. MicroRNA-100 is a potential molecular marker of non-small cell lung cancer and functions as a tumor suppressor by targeting polo-like kinase 1. BMC Cancer 2012, 12, 519. [Google Scholar] [CrossRef] [PubMed]
  227. Luo, L.; Zhang, T.; Liu, H.; Lv, T.; Yuan, D.; Yao, Y.; Lv, Y.; Song, Y. MiR-101 and Mcl-1 in non-small-cell lung cancer: Expression profile and clinical significance. Med. Oncol. 2012, 29, 1681–1686. [Google Scholar] [CrossRef] [PubMed]
  228. Lu, H.M.; Yi, W.W.; Ma, Y.S.; Wu, W.; Yu, F.; Fan, H.W.; Lv, Z.W.; Yang, H.Q.; Chang, Z.Y.; Zhang, C.; et al. Prognostic implications of decreased microRNA-101-3p expression in patients with non-small cell lung cancer. Oncol. Lett. 2018, 16, 7048–7056. [Google Scholar] [CrossRef] [PubMed]
  229. Cui, Y.; Zhang, F.; Zhu, C.; Geng, L.; Tian, T.; Liu, H. Upregulated lncRNA SNHG1 contributes to progression of non-small cell lung cancer through inhibition of miR-101-3p and activation of Wnt/beta-catenin signaling pathway. Oncotarget 2017, 8, 17785–17794. [Google Scholar] [CrossRef] [PubMed]
  230. Li, Y.; Tian, J.; Guo, Z.J.; Zhang, Z.B.; Xiao, C.Y.; Wang, X.C. Expression of microRNAs-106b in nonsmall cell lung cancer. J. Cancer Res. Ther. 2018, 14, S295–S298. [Google Scholar] [CrossRef] [PubMed]
  231. Zhong, K.Z.; Chen, W.W.; Hu, X.Y.; Jiang, A.L.; Zhao, J. Clinicopathological and prognostic significance of microRNA-107 in human non small cell lung cancer. Int. J. Clin. Exp. Pathol. 2014, 7, 4545–4551. [Google Scholar] [PubMed]
  232. Xia, H.; Li, Y.; Lv, X. MicroRNA-107 inhibits tumor growth and metastasis by targeting the BDNF-mediated PI3K/AKT pathway in human non-small lung cancer. Int. J. Oncol. 2016, 49, 1325–1333. [Google Scholar] [CrossRef] [PubMed]
  233. Xie, C.; Han, Y.; Liu, Y.; Han, L.; Liu, J. miRNA-124 down-regulates SOX8 expression and suppresses cell proliferation in non-small cell lung cancer. Int. J. Clin. Exp. Pathol. 2014, 7, 6534–6542. [Google Scholar] [PubMed]
  234. Yu, W.; Peng, W.; Jiang, H.; Sha, H.; Li, J. LncRNA HOXA11-AS promotes proliferation and invasion by targeting miR-124 in human non-small cell lung cancer cells. Tumour Biol. 2017, 39, 1010428317721440. [Google Scholar] [CrossRef] [PubMed]
  235. Jiang, L.; Huang, Q.; Zhang, S.; Zhang, Q.; Chang, J.; Qiu, X.; Wang, E. Hsa-miR-125a-3p and hsa-miR-125a-5p are downregulated in non-small cell lung cancer and have inverse effects on invasion and migration of lung cancer cells. BMC Cancer 2010, 10, 318. [Google Scholar] [CrossRef] [PubMed]
  236. Hou, L.; Luo, P.; Ma, Y.; Jia, C.; Yu, F.; Lv, Z.; Wu, C.; Fu, D. MicroRNA-125a-3p downregulation correlates with tumorigenesis and poor prognosis in patients with non-small cell lung cancer. Oncol. Lett. 2017, 14, 4441–4448. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  237. Zheng, H.; Wu, J.; Shi, J.; Lu, C.; Wang, Y.; Sun, Q.; Zhang, G.; Zhao, G. miR-125a-5p upregulation suppresses the proliferation and induces the cell apoptosis of lung adenocarcinoma by targeting NEDD9. Oncol. Rep. 2017, 38, 1790–1796. [Google Scholar] [CrossRef] [PubMed]
  238. Yu, X.; Wei, F.; Yu, J.; Zhao, H.; Jia, L.; Ye, Y.; Du, R.; Ren, X.; Li, H. Matrix metalloproteinase 13: A potential intermediate between low expression of microRNA-125b and increasing metastatic potential of non-small cell lung cancer. Cancer Genet. 2015, 208, 76–84. [Google Scholar] [CrossRef] [PubMed]
  239. Chen, P.; Gu, Y.Y.; Ma, F.C.; He, R.Q.; Li, Z.Y.; Zhai, G.Q.; Lin, X.; Hu, X.H.; Pan, L.J.; Chen, G. Expression levels and cotargets of miRNA1263p and miRNA1265p in lung adenocarcinoma tissues: Alphan exploration with RTqPCR, microarray and bioinformatic analyses. Oncol. Rep. 2019, 41, 939–953. [Google Scholar] [CrossRef] [PubMed]
  240. Chen, S.W.; Wang, T.B.; Tian, Y.H.; Zheng, Y.G. Down-regulation of microRNA-126 and microRNA-133b acts as novel predictor biomarkers in progression and metastasis of non small cell lung cancer. Int. J. Clin. Exp. Pathol. 2015, 8, 14983–14988. [Google Scholar] [PubMed]
  241. Hu, J.; Cheng, Y.; Li, Y.; Jin, Z.; Pan, Y.; Liu, G.; Fu, S.; Zhang, Y.; Feng, K.; Feng, Y. microRNA-128 plays a critical role in human non-small cell lung cancer tumourigenesis, angiogenesis and lymphangiogenesis by directly targeting vascular endothelial growth factor-C. Eur. J. Cancer 2014, 50, 2336–2350. [Google Scholar] [CrossRef] [PubMed]
  242. Shen, Q.; Jiang, Y. LncRNA NNT-AS1 promotes the proliferation, and invasion of lung cancer cells via regulating miR-129-5p expression. Biomed. Pharmacother. 2018, 105, 176–181. [Google Scholar] [CrossRef] [PubMed]
  243. Ye, L.; Wang, Y.; Nie, L.; Qian, S.; Xu, M. MiR-130 exerts tumor suppressive function on the tumorigenesis of human non-small cell lung cancer by targeting PTEN. Am. J. Transl. Res. 2017, 9, 1856–1865. [Google Scholar] [PubMed]
  244. Wang, X.C.; Tian, L.L.; Wu, H.L.; Jiang, X.Y.; Du, L.Q.; Zhang, H.; Wang, Y.Y.; Wu, H.Y.; Li, D.G.; She, Y.; et al. Expression of miRNA-130a in nonsmall cell lung cancer. Am. J. Med. Sci. 2010, 340, 385–388. [Google Scholar] [CrossRef] [PubMed]
  245. Yang, Z.Q.; Wu, C.A.; Cheng, Y.X. Prognostic Value of microRNA-133a Expression and Its Clinicopathologic Significance in Non-Small Cell Lung Cancer: A Comprehensive Study Based on Meta-Analysis and the TCGA Database. Oncol. Res. Treat. 2018, 41, 762–768. [Google Scholar] [CrossRef] [PubMed]
  246. Liu, L.; Shao, X.; Gao, W.; Zhang, Z.; Liu, P.; Wang, R.; Huang, P.; Yin, Y.; Shu, Y. MicroRNA-133b inhibits the growth of non-small-cell lung cancer by targeting the epidermal growth factor receptor. FEBS J. 2012, 279, 3800–3812. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  247. Xia, H.; Jing, H.; Li, Y.; Lv, X. Long noncoding RNA HOXD-AS1 promotes non-small cell lung cancer migration and invasion through regulating miR-133b/MMP9 axis. Biomed. Pharmacother. 2018, 106, 156–162. [Google Scholar] [CrossRef] [PubMed]
  248. Han, L.; Zhang, G.; Zhang, N.; Li, H.; Liu, Y.; Fu, A.; Zheng, Y. Prognostic potential of microRNA-138 and its target mRNA PDK1 in sera for patients with non-small cell lung cancer. Med. Oncol. 2014, 31, 129. [Google Scholar] [CrossRef] [PubMed]
  249. Ye, Z.; Fang, B.; Pan, J.; Zhang, N.; Huang, J.; Xie, C.; Lou, T.; Cao, Z. miR-138 suppresses the proliferation, metastasis and autophagy of non-small cell lung cancer by targeting Sirt1. Oncol. Rep. 2017, 37, 3244–3252. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  250. Xiao, L.; Zhou, H.; Li, X.P.; Chen, J.; Fang, C.; Mao, C.X.; Cui, J.J.; Zhang, W.; Zhou, H.H.; Yin, J.Y.; et al. MicroRNA-138 acts as a tumor suppressor in non small cell lung cancer via targeting YAP1. Oncotarget 2016, 7, 40038–40046. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  251. Watanabe, K.; Amano, Y.; Ishikawa, R.; Sunohara, M.; Kage, H.; Ichinose, J.; Sano, A.; Nakajima, J.; Fukayama, M.; Yatomi, Y.; et al. Histone methylation-mediated silencing of miR-139 enhances invasion of non-small-cell lung cancer. Cancer Med. 2015, 4, 1573–1582. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  252. Zhang, X.; Li, P.; Rong, M.; He, R.; Hou, X.; Xie, Y.; Chen, G. MicroRNA-141 is a biomarker for progression of squamous cell carcinoma and adenocarcinoma of the lung: Clinical analysis of 125 patients. Tohoku J. Exp. Med. 2015, 235, 161–169. [Google Scholar] [CrossRef] [PubMed]
  253. Wang, M.; Wang, J.; Deng, J.; Li, X.; Long, W.; Chang, Y. MiR-145 acts as a metastasis suppressor by targeting metadherin in lung cancer. Med. Oncol. 2015, 32, 344. [Google Scholar] [CrossRef] [PubMed]
  254. Liu, K.; Chen, H.; You, Q.; Ye, Q.; Wang, F.; Wang, S.; Zhang, S.; Yu, K.; Li, W.; Gu, M. miR145 inhibits human nonsmall-cell lung cancer growth by dual-targeting RIOK2 and NOB1. Int. J. Oncol. 2018, 53, 257–265. [Google Scholar] [CrossRef] [PubMed]
  255. Gan, T.Q.; Xie, Z.C.; Tang, R.X.; Zhang, T.T.; Li, D.Y.; Li, Z.Y.; Chen, G. Clinical value of miR-145-5p in NSCLC and potential molecular mechanism exploration: A retrospective study based on GEO, qRT-PCR, and TCGA data. Tumour Biol. 2017, 39, 1010428317691683. [Google Scholar] [CrossRef] [PubMed]
  256. Chu, G.; Zhang, J.; Chen, X. Serum level of microRNA-147 as diagnostic biomarker in human non-small cell lung cancer. J. Drug Target. 2016, 24, 613–617. [Google Scholar] [CrossRef] [PubMed]
  257. Chen, Y.; Min, L.; Zhang, X.; Hu, S.; Wang, B.; Liu, W.; Wang, R.; Gu, X.; Shen, W.; Lv, H.; et al. Decreased miRNA-148a is associated with lymph node metastasis and poor clinical outcomes and functions as a suppressor of tumor metastasis in non-small cell lung cancer. Oncol. Rep. 2013, 30, 1832–1840. [Google Scholar] [CrossRef] [PubMed]
  258. Chen, Y.; Min, L.; Ren, C.; Xu, X.; Yang, J.; Sun, X.; Wang, T.; Wang, F.; Sun, C.; Zhang, X. miRNA-148a serves as a prognostic factor and suppresses migration and invasion through Wnt1 in non-small cell lung cancer. PLoS ONE 2017, 12, e0171751. [Google Scholar] [CrossRef] [PubMed]
  259. Li, J.; Yu, T.; Cao, J.; Liu, L.; Liu, Y.; Kong, H.W.; Zhu, M.X.; Lin, H.C.; Chu, D.D.; Yao, M.; et al. MicroRNA-148a Suppresses Invasion and Metastasis of Human Non-Small-Cell Lung Cancer. Cell. Physiol. Biochem. 2015, 37, 1847–1856. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  260. Ge, H.; Li, B.; Hu, W.X.; Li, R.J.; Jin, H.; Gao, M.M.; Ding, C.M. MicroRNA-148b is down-regulated in non-small cell lung cancer and associated with poor survival. Int. J. Clin. Exp. Pathol. 2015, 8, 800–805. [Google Scholar] [PubMed]
  261. Yin, Q.W.; Sun, X.F.; Yang, G.T.; Li, X.B.; Wu, M.S.; Zhao, J. Increased expression of microRNA-150 is associated with poor prognosis in non-small cell lung cancer. Int. J. Clin. Exp. Pathol. 2015, 8, 842–846. [Google Scholar] [PubMed]
  262. Shan, N.; Shen, L.; Wang, J.; He, D.; Duan, C. MiR-153 inhibits migration and invasion of human non-small-cell lung cancer by targeting ADAM19. Biochem. Biophys. Res. Commun. 2015, 456, 385–391. [Google Scholar] [CrossRef] [PubMed]
  263. Chen, W.J.; Zhang, E.N.; Zhong, Z.K.; Jiang, M.Z.; Yang, X.F.; Zhou, D.M.; Wang, X.W. MicroRNA-153 expression and prognosis in non-small cell lung cancer. Int. J. Clin. Exp. Pathol. 2015, 8, 8671–8675. [Google Scholar] [PubMed]
  264. Li, S.; Yang, J.; Xia, Y.; Fan, Q.; Yang, K.P. Long Noncoding RNA NEAT1 Promotes Proliferation and Invasion via Targeting miR-181a-5p in Non-Small Cell Lung Cancer. Oncol. Res. 2018, 26, 289–296. [Google Scholar] [CrossRef] [PubMed]
  265. Yang, J.; Liu, H.; Wang, H.; Sun, Y. Down-regulation of microRNA-181b is a potential prognostic marker of non-small cell lung cancer. Pathol. Res. Pract. 2013, 209, 490–494. [Google Scholar] [CrossRef] [PubMed]
  266. Xu, F.; Zhang, H.; Su, Y.; Kong, J.; Yu, H.; Qian, B. Up-regulation of microRNA-183-3p is a potent prognostic marker for lung adenocarcinoma of female non-smokers. Clin. Transl. Oncol. 2014, 16, 980–985. [Google Scholar] [CrossRef] [PubMed]
  267. Zhao, L.; Zhang, Y.; Liu, J.; Yin, W.; Jin, D.; Wang, D.; Zhang, W. MiR-185 inhibits cell proliferation and invasion of non-small cell lung cancer by targeting KLF7. Oncol. Res. 2018. [Google Scholar] [CrossRef] [PubMed]
  268. Dong, Y.; Jin, X.; Sun, Z.; Zhao, Y.; Song, X. MiR-186 Inhibited Migration of NSCLC via Targeting cdc42 and Effecting EMT Process. Mol. Cells 2017, 40, 195–201. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  269. Li, H.; Yin, C.; Zhang, B.; Sun, Y.; Shi, L.; Liu, N.; Liang, S.; Lu, S.; Liu, Y.; Zhang, J.; et al. PTTG1 promotes migration and invasion of human non-small cell lung cancer cells and is modulated by miR-186. Carcinogenesis 2013, 34, 2145–2155. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  270. Yu, T.; Li, J.; Yan, M.; Liu, L.; Lin, H.; Zhao, F.; Sun, L.; Zhang, Y.; Cui, Y.; Zhang, F.; et al. MicroRNA-193a-3p and -5p suppress the metastasis of human non-small-cell lung cancer by downregulating the ERBB4/PIK3R3/mTOR/S6K2 signaling pathway. Oncogene 2015, 34, 413–423. [Google Scholar] [CrossRef] [PubMed]
  271. Ren, F.; Ding, H.; Huang, S.; Wang, H.; Wu, M.; Luo, D.; Dang, Y.; Yang, L.; Chen, G. Expression and clinicopathological significance of miR-193a-3p and its potential target astrocyte elevated gene-1 in non-small lung cancer tissues. Cancer Cell Int. 2015, 15, 80. [Google Scholar] [CrossRef] [PubMed]
  272. Trang, P.; Wiggins, J.F.; Daige, C.L.; Cho, C.; Omotola, M.; Brown, D.; Weidhaas, J.B.; Bader, A.G.; Slack, F.J. Systemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice. Mol. Ther. 2011, 19, 1116–1122. [Google Scholar] [CrossRef] [PubMed]
  273. Su, K.; Zhang, T.; Wang, Y.; Hao, G. Diagnostic and prognostic value of plasma microRNA-195 in patients with non-small cell lung cancer. World J. Surg. Oncol. 2016, 14, 224. [Google Scholar] [CrossRef] [PubMed]
  274. Wu, S.; Zhang, G.; Li, P.; Chen, S.; Zhang, F.; Li, J.; Jiang, C.; Chen, X.; Wang, Y.; Du, Y.; et al. miR-198 targets SHMT1 to inhibit cell proliferation and enhance cell apoptosis in lung adenocarcinoma. Tumour Biol. 2016, 37, 5193–5202. [Google Scholar] [CrossRef] [PubMed]
  275. Ceppi, P.; Mudduluru, G.; Kumarswamy, R.; Rapa, I.; Scagliotti, G.V.; Papotti, M.; Allgayer, H. Loss of miR-200c expression induces an aggressive, invasive, and chemoresistant phenotype in non-small cell lung cancer. Mol. Cancer Res. 2010, 8, 1207–1216. [Google Scholar] [CrossRef] [PubMed]
  276. Si, L.; Tian, H.; Yue, W.; Li, L.; Li, S.; Gao, C.; Qi, L. Potential use of microRNA-200c as a prognostic marker in non-small cell lung cancer. Oncol. Lett. 2017, 14, 4325–4330. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  277. Zhao, Z.; Lv, B.; Zhang, L.; Zhao, N.; Lv, Y. miR-202 functions as a tumor suppressor in non-small cell lung cancer by targeting STAT3. Mol. Med. Rep. 2017, 16, 2281–2289. [Google Scholar] [CrossRef] [PubMed]
  278. Zheng, J.; Wang, F.; Lu, S.; Wang, X. LASP-1, regulated by miR-203, promotes tumor proliferation and aggressiveness in human non-small cell lung cancer. Exp. Mol. Pathol. 2016, 100, 116–124. [Google Scholar] [CrossRef] [PubMed]
  279. Osugi, J.; Kimura, Y.; Owada, Y.; Inoue, T.; Watanabe, Y.; Yamaura, T.; Fukuhara, M.; Muto, S.; Okabe, N.; Matsumura, Y.; et al. Prognostic Impact of Hypoxia-Inducible miRNA-210 in Patients with Lung Adenocarcinoma. J. Oncol. 2015, 2015, 316745. [Google Scholar] [CrossRef] [PubMed]
  280. Li, Z.H.; Zhang, H.; Yang, Z.G.; Wen, G.Q.; Cui, Y.B.; Shao, G.G. Prognostic significance of serum microRNA-210 levels in nonsmall-cell lung cancer. J. Int. Med. Res. 2013, 41, 1437–1444. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  281. Cui, H.X.; Zhang, M.Y.; Liu, K.; Liu, J.; Zhang, Z.L.; Fu, L. LncRNA SNHG15 promotes proliferation and migration of lung cancer via targeting microRNA-211-3p. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 6838–6844. [Google Scholar] [CrossRef] [PubMed]
  282. Tang, T.; Huan, L.; Zhang, S.; Zhou, H.; Gu, L.; Chen, X.; Zhang, L. MicroRNA-212 functions as a tumor-suppressor in human non-small cell lung cancer by targeting SOX4. Oncol. Rep. 2017, 38, 2243–2250. [Google Scholar] [CrossRef] [PubMed]
  283. Zhang, Y.; Zhao, Y.; Sun, S.; Liu, Z.; Zhang, Y.; Jiao, S. Overexpression of MicroRNA-221 is associated with poor prognosis in non-small cell lung cancer patients. Tumour Biol. 2016, 37, 10155–10160. [Google Scholar] [CrossRef] [PubMed]
  284. Zhu, D.; Chen, H.; Yang, X.; Chen, W.; Wang, L.; Xu, J.; Yu, L. Decreased microRNA-224 and its clinical significance in non-small cell lung cancer patients. Diagn. Pathol. 2014, 9, 198. [Google Scholar] [CrossRef] [PubMed]
  285. Shi, Y.K.; Zang, Q.L.; Li, G.X.; Huang, Y.; Wang, S.Z. Increased expression of microRNA-301a in nonsmall-cell lung cancer and its clinical significance. J. Cancer Res. Ther. 2016, 12, 693–698. [Google Scholar] [CrossRef] [PubMed]
  286. Ma, W.; Ma, C.N.; Zhou, N.N.; Li, X.D.; Zhang, Y.J. Up- regulation of miR-328-3p sensitizes non-small cell lung cancer to radiotherapy. Sci. Rep. 2016, 6, 31651. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  287. Wang, H.; Li, M.; Zhang, R.; Wang, Y.; Zang, W.; Ma, Y.; Zhao, G.; Zhang, G. Effect of miR-335 upregulation on the apoptosis and invasion of lung cancer cell A549 and H1299. Tumour Biol. 2013, 34, 3101–3109. [Google Scholar] [CrossRef] [PubMed]
  288. Zhang, P.; Shao, G.; Lin, X.; Liu, Y.; Yang, Z. MiR-338-3p inhibits the growth and invasion of non-small cell lung cancer cells by targeting IRS2. Am. J. Cancer Res. 2017, 7, 53–63. [Google Scholar] [PubMed]
  289. Li, Y.; Zhao, W.; Bao, P.; Li, C.; Ma, X.Q.; Li, Y.; Chen, L.A. miR-339-5p inhibits cell migration and invasion in vitro and may be associated with the tumor-node-metastasis staging and lymph node metastasis of non-small cell lung cancer. Oncol. Lett. 2014, 8, 719–725. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  290. Li, Y.; Zhang, X.; Yang, Z.; Li, Y.; Han, B.; Chen, L.A. miR-339-5p inhibits metastasis of non-small cell lung cancer by regulating the epithelial-to-mesenchymal transition. Oncol. Lett. 2018, 15, 2508–2514. [Google Scholar] [CrossRef] [PubMed]
  291. Qin, Y.; Zhou, X.; Huang, C.; Li, L.; Liu, H.; Liang, N.; Chen, Y.; Ma, D.; Han, Z.; Xu, X.; et al. Lower miR-340 expression predicts poor prognosis of non-small cell lung cancer and promotes cell proliferation by targeting CDK4. Gene 2018, 675, 278–284. [Google Scholar] [CrossRef] [PubMed]
  292. Zhuang, Z.L.; Tian, F.M.; Sun, C.L. Downregulation of miR-361-5p associates with aggressive clinicopathological features and unfavorable prognosis in non-small cell lung cancer. Eur. Rev. Med. Pharmacol. Sci. 2016, 20, 5132–5136. [Google Scholar] [PubMed]
  293. Liu, Y.; Zhang, G.; Li, H.; Han, L.; Fu, A.; Zhang, N.; Zheng, Y. Serum microRNA-365 in combination with its target gene TTF-1 as a non-invasive prognostic marker for non-small cell lung cancer. Biomed. Pharmacother. 2015, 75, 185–190. [Google Scholar] [CrossRef] [PubMed]
  294. Sun, R.; Liu, Z.; Ma, G.; Lv, W.; Zhao, X.; Lei, G.; Xu, C. Associations of deregulation of mir-365 and its target mRNA TTF-1 and survival in patients with NSCLC. Int. J. Clin. Exp. Pathol. 2015, 8, 2392–2399. [Google Scholar] [PubMed]
  295. Skrzypek, K.; Tertil, M.; Golda, S.; Ciesla, M.; Weglarczyk, K.; Collet, G.; Guichard, A.; Kozakowska, M.; Boczkowski, J.; Was, H.; et al. Interplay between heme oxygenase-1 and miR-378 affects non-small cell lung carcinoma growth, vascularization, and metastasis. Antioxid. Redox Signal. 2013, 19, 644–660. [Google Scholar] [CrossRef] [PubMed]
  296. Zhou, F.; Nie, L.; Feng, D.; Guo, S.; Luo, R. MicroRNA-379 acts as a tumor suppressor in non-small cell lung cancer by targeting the IGF1R-mediated AKT and ERK pathways. Oncol. Rep. 2017, 38, 1857–1866. [Google Scholar] [CrossRef] [PubMed]
  297. Tian, C.; Li, J.; Ren, L.; Peng, R.; Chen, B.; Lin, Y. MicroRNA-381 serves as a prognostic factor and inhibits migration and invasion in non-small cell lung cancer by targeting LRH-1. Oncol. Rep. 2017, 38, 3071–3077. [Google Scholar] [CrossRef] [PubMed]
  298. Shang, Y.; Zang, A.; Li, J.; Jia, Y.; Li, X.; Zhang, L.; Huo, R.; Yang, J.; Feng, J.; Ge, K.; et al. MicroRNA-383 is a tumor suppressor and potential prognostic biomarker in human non-small cell lung caner. Biomed. Pharmacother. 2016, 83, 1175–1181. [Google Scholar] [CrossRef] [PubMed]
  299. Wan, L.; Zhu, L.; Xu, J.; Lu, B.; Yang, Y.; Liu, F.; Wang, Z. MicroRNA-409-3p functions as a tumor suppressor in human lung adenocarcinoma by targeting c-Met. Cell. Physiol. Biochem. 2014, 34, 1273–1290. [Google Scholar] [CrossRef] [PubMed]
  300. Wang, S.Y.; Li, Y.; Jiang, Y.S.; Li, R.Z. Investigation of serum miR-411 as a diagnosis and prognosis biomarker for non-small cell lung cancer. Eur. Rev. Med. Pharmacol. Sci. 2017, 21, 4092–4097. [Google Scholar] [PubMed]
  301. Li, Y.; Cui, X.; Li, Y.; Zhang, T.; Li, S. Upregulated expression of miR-421 is associated with poor prognosis in non-small-cell lung cancer. Cancer Manag. Res. 2018, 10, 2627–2633. [Google Scholar] [CrossRef] [PubMed]
  302. Wu, L.; Hu, B.; Zhao, B.; Liu, Y.; Yang, Y.; Zhang, L.; Chen, J. Circulating microRNA-422a is associated with lymphatic metastasis in lung cancer. Oncotarget 2017, 8, 42173–42188. [Google Scholar] [CrossRef] [PubMed]
  303. Liu, N.; Liu, Z.; Zhang, W.; Li, Y.; Cao, J.; Yang, H.; Li, X. MicroRNA433 reduces cell proliferation and invasion in nonsmall cell lung cancer via directly targeting E2F transcription factor 3. Mol. Med. Rep. 2018, 18, 1155–1164. [Google Scholar] [CrossRef] [PubMed]
  304. Shan, C.; Fei, F.; Li, F.; Zhuang, B.; Zheng, Y.; Wan, Y.; Chen, J. miR-448 is a novel prognostic factor of lung squamous cell carcinoma and regulates cells growth and metastasis by targeting DCLK1. Biomed. Pharmacother. 2017, 89, 1227–1234. [Google Scholar] [CrossRef] [PubMed]
  305. Luo, W.; Huang, B.; Li, Z.; Li, H.; Sun, L.; Zhang, Q.; Qiu, X.; Wang, E. MicroRNA-449a is downregulated in non-small cell lung cancer and inhibits migration and invasion by targeting c-Met. PLoS ONE 2013, 8, e64759. [Google Scholar] [CrossRef] [PubMed]
  306. Wang, R.; Wang, Z.X.; Yang, J.S.; Pan, X.; De, W.; Chen, L.B. MicroRNA-451 functions as a tumor suppressor in human non-small cell lung cancer by targeting ras-related protein 14 (RAB14). Oncogene 2011, 30, 2644–2658. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  307. Wang, X.C.; Tian, L.L.; Jiang, X.Y.; Wang, Y.Y.; Li, D.G.; She, Y.; Chang, J.H.; Meng, A.M. The expression and function of miRNA-451 in non-small cell lung cancer. Cancer Lett. 2011, 311, 203–209. [Google Scholar] [CrossRef] [PubMed]
  308. Kanaoka, R.; Iinuma, H.; Dejima, H.; Sakai, T.; Uehara, H.; Matsutani, N.; Kawamura, M. Usefulness of Plasma Exosomal MicroRNA-451a as a Noninvasive Biomarker for Early Prediction of Recurrence and Prognosis of Non-Small Cell Lung Cancer. Oncology 2018, 94, 311–323. [Google Scholar] [CrossRef] [PubMed]
  309. He, Z.; Xia, Y.; Pan, C.; Ma, T.; Liu, B.; Wang, J.; Chen, L.; Chen, Y. Up-Regulation of MiR-452 Inhibits Metastasis of Non-Small Cell Lung Cancer by Regulating BMI1. Cell. Physiol. Biochem. 2015, 37, 387–398. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  310. Gan, X.N.; Luo, J.; Tang, R.X.; Wang, H.L.; Zhou, H.; Qin, H.; Gan, T.Q.; Chen, G. Clinical value of miR-452-5p expression in lung adenocarcinoma: A retrospective quantitative real-time polymerase chain reaction study and verification based on The Cancer Genome Atlas and Gene Expression Omnibus databases. Tumour Biol. 2017, 39, 1010428317705755. [Google Scholar] [CrossRef] [PubMed]
  311. Zhu, D.Y.; Li, X.N.; Qi, Y.; Liu, D.L.; Yang, Y.; Zhao, J.; Zhang, C.Y.; Wu, K.; Zhao, S. MiR-454 promotes the progression of human non-small cell lung cancer and directly targets PTEN. Biomed. Pharmacother. 2016, 81, 79–85. [Google Scholar] [CrossRef] [PubMed]
  312. Huang, R.S.; Zheng, Y.L.; Li, C.; Ding, C.; Xu, C.; Zhao, J. MicroRNA-485-5p suppresses growth and metastasis in non-small cell lung cancer cells by targeting IGF2BP2. Life Sci. 2018, 199, 104–111. [Google Scholar] [CrossRef] [PubMed]
  313. Shen, J.; Liu, Z.; Todd, N.W.; Zhang, H.; Liao, J.; Yu, L.; Guarnera, M.A.; Li, R.; Cai, L.; Zhan, M.; et al. Diagnosis of lung cancer in individuals with solitary pulmonary nodules by plasma microRNA biomarkers. BMC Cancer 2011, 11, 374. [Google Scholar] [CrossRef] [PubMed]
  314. Wang, J.; Tian, X.; Han, R.; Zhang, X.; Wang, X.; Shen, H.; Xue, L.; Liu, Y.; Yan, X.; Shen, J.; et al. Downregulation of miR-486-5p contributes to tumor progression and metastasis by targeting protumorigenic ARHGAP5 in lung cancer. Oncogene 2014, 33, 1181–1189. [Google Scholar] [CrossRef] [PubMed]
  315. Pang, W.; Tian, X.; Bai, F.; Han, R.; Wang, J.; Shen, H.; Zhang, X.; Liu, Y.; Yan, X.; Jiang, F.; et al. Pim-1 kinase is a target of miR-486-5p and eukaryotic translation initiation factor 4E, and plays a critical role in lung cancer. Mol. Cancer 2014, 13, 240. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  316. Gong, F.; Ren, P.; Zhang, Y.; Jiang, J.; Zhang, H. MicroRNAs-491-5p suppresses cell proliferation and invasion by inhibiting IGF2BP1 in non-small cell lung cancer. Am. J. Transl. Res. 2016, 8, 485–495. [Google Scholar] [PubMed]
  317. Zhang, J.; Wang, T.; Zhang, Y.; Wang, H.; Wu, Y.; Liu, K.; Pei, C. Upregulation of serum miR-494 predicts poor prognosis in non-small cell lung cancer patients. Cancer Biomark. 2018, 21, 763–768. [Google Scholar] [CrossRef] [PubMed]
  318. Wang, J.; Chen, H.; Liao, Y.; Chen, N.; Liu, T.; Zhang, H.; Zhang, H. Expression and clinical evidence of miR-494 and PTEN in non-small cell lung cancer. Tumour Biol. 2015, 36, 6965–6972. [Google Scholar] [CrossRef] [PubMed]
  319. Ye, M.F.; Zhang, J.G.; Guo, T.X.; Pan, X.J. MiR-504 inhibits cell proliferation and invasion by targeting LOXL2 in non small cell lung cancer. Biomed. Pharmacother. 2018, 97, 1289–1295. [Google Scholar] [CrossRef] [PubMed]
  320. Guo, S.; Yang, P.; Jiang, X.; Li, X.; Wang, Y.; Zhang, X.; Sun, B.; Zhang, Y.; Jia, Y. Genetic and epigenetic silencing of mircoRNA-506-3p enhances COTL1 oncogene expression to foster non-small lung cancer progression. Oncotarget 2017, 8, 644–657. [Google Scholar] [CrossRef] [PubMed]
  321. Zhang, L.; Yu, S. Role of miR-520b in non-small cell lung cancer. Exp. Ther. Med. 2018, 16, 3987–3995. [Google Scholar] [CrossRef] [PubMed]
  322. Liu, C.; Yang, H.; Xu, Z.; Li, D.; Zhou, M.; Xiao, K.; Shi, Z.; Zhu, L.; Yang, L.; Zhou, R. microRNA-548l is involved in the migration and invasion of non-small cell lung cancer by targeting the AKT1 signaling pathway. J. Cancer Res. Clin. Oncol. 2015, 141, 431–441. [Google Scholar] [CrossRef] [PubMed]
  323. Wang, L.L.; Zhang, M. miR-582-5p is a potential prognostic marker in human non-small cell lung cancer and functions as a tumor suppressor by targeting MAP3K2. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 7760–7767. [Google Scholar] [CrossRef] [PubMed]
  324. Qian, L.; Lin, L.; Du, Y.; Hao, X.; Zhao, Y.; Liu, X. MicroRNA-588 suppresses tumor cell migration and invasion by targeting GRN in lung squamous cell carcinoma. Mol. Med. Rep. 2016, 14, 3021–3028. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  325. Li, Z.; Li, B.; Niu, L.; Ge, L. miR-592 functions as a tumor suppressor in human non-small cell lung cancer by targeting SOX9. Oncol. Rep. 2017, 37, 297–304. [Google Scholar] [CrossRef] [PubMed]
  326. Wang, F.; Lou, J.F.; Cao, Y.; Shi, X.H.; Wang, P.; Xu, J.; Xie, E.F.; Xu, T.; Sun, R.H.; Rao, J.Y.; et al. miR-638 is a new biomarker for outcome prediction of non-small cell lung cancer patients receiving chemotherapy. Exp. Mol. Med. 2015, 47, e162. [Google Scholar] [CrossRef] [PubMed]
  327. Huang, J.Y.; Cui, S.Y.; Chen, Y.T.; Song, H.Z.; Huang, G.C.; Feng, B.; Sun, M.; De, W.; Wang, R.; Chen, L.B. MicroRNA-650 was a prognostic factor in human lung adenocarcinoma and confers the docetaxel chemoresistance of lung adenocarcinoma cells via regulating Bcl-2/Bax expression. PLoS ONE 2013, 8, e72615. [Google Scholar] [CrossRef] [PubMed]
  328. Yang, W.; Zhou, C.; Luo, M.; Shi, X.; Li, Y.; Sun, Z.; Zhou, F.; Chen, Z.; He, J. MiR-652-3p is up-regulated in non-small cell lung cancer and promotes proliferation and metastasis by directly targeting Lgl1. Oncotarget 2016, 7, 16703–16715. [Google Scholar] [CrossRef] [PubMed]
  329. Wang, Y.; Li, Y.; Wu, B.; Shi, C.; Li, C. MicroRNA-661 promotes non-small cell lung cancer progression by directly targeting RUNX3. Mol. Med. Rep. 2017, 16, 2113–2120. [Google Scholar] [CrossRef] [PubMed]
  330. He, D.; Wang, J.; Zhang, C.; Shan, B.; Deng, X.; Li, B.; Zhou, Y.; Chen, W.; Hong, J.; Gao, Y.; et al. Down-regulation of miR-675-5p contributes to tumor progression and development by targeting pro-tumorigenic GPR55 in non-small cell lung cancer. Mol. Cancer 2015, 14, 73. [Google Scholar] [CrossRef] [PubMed]
  331. Yang, R.; Li, P.; Zhang, G.; Lu, C.; Wang, H.; Zhao, G. Long Non-Coding RNA XLOC_008466 Functions as an Oncogene in Human Non-Small Cell Lung Cancer by Targeting miR-874. Cell. Physiol. Biochem. 2017, 42, 126–136. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  332. Wang, C.; Li, S.; Xu, J.; Niu, W.; Li, S. microRNA-935 is reduced in non-small cell lung cancer tissue, is linked to poor outcome, and acts on signal transduction mediator E2F7 and the AKT pathway. Br. J. Biomed. Sci. 2019, 76, 17–23. [Google Scholar] [CrossRef] [PubMed]
  333. Jiang, W.; He, Y.; Shi, Y.; Guo, Z.; Yang, S.; Wei, K.; Pan, C.; Xia, Y.; Chen, Y. MicroRNA-1204 promotes cell proliferation by regulating PITX1 in non-small cell lung cancer. Cell Biol. Int. 2018. [Google Scholar] [CrossRef] [PubMed]
  334. Bao, M.; Song, Y.; Xia, J.; Li, P.; Liu, Q.; Wan, Z. miR-1269 promotes cell survival and proliferation by targeting tp53 and caspase-9 in lung cancer. Onco-Targets Ther. 2018, 11, 1721–1732. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  335. Jin, J.J.; Liu, Y.H.; Si, J.M.; Ni, R.; Wang, J. Overexpression of miR-1290 contributes to cell proliferation and invasion of non small cell lung cancer by targeting interferon regulatory factor 2. Int. J. Biochem. Cell Biol. 2018, 95, 113–120. [Google Scholar] [CrossRef] [PubMed]
  336. Mo, D.; Gu, B.; Gong, X.; Wu, L.; Wang, H.; Jiang, Y.; Zhang, B.; Zhang, M.; Zhang, Y.; Xu, J.; et al. miR-1290 is a potential prognostic biomarker in non-small cell lung cancer. J. Thorac. Dis. 2015, 7, 1570–1579. [Google Scholar] [CrossRef] [PubMed]
  337. Li, X.; Ren, Y.; Zuo, T. Long noncoding RNA LINC00978 promotes cell proliferation and invasion in nonsmall cell lung cancer by inhibiting miR67545p. Mol. Med. Rep. 2018, 18, 4725–4732. [Google Scholar] [CrossRef] [PubMed]
  338. Chen, Y.; Gorski, D.H. Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes GAX and HOXA5. Blood 2008, 111, 1217–1226. [Google Scholar] [CrossRef] [PubMed]
  339. Li, Y.; Egranov, S.D.; Yang, L.; Lin, C. Molecular Mechanisms of Long Noncoding RNAs-mediated Cancer Metastasis. Genes Chromosomes Cancer 2018. [Google Scholar] [CrossRef] [PubMed]
  340. Sanchez Calle, A.; Kawamura, Y.; Yamamoto, Y.; Takeshita, F.; Ochiya, T. Emerging roles of long non-coding RNA in cancer. Cancer Sci. 2018, 109, 2093–2100. [Google Scholar] [CrossRef] [PubMed]
  341. Berghmans, T.; Ameye, L.; Willems, L.; Paesmans, M.; Mascaux, C.; Lafitte, J.J.; Meert, A.P.; Scherpereel, A.; Cortot, A.B.; Cstoth, I.; et al. Identification of microRNA-based signatures for response and survival for non-small cell lung cancer treated with cisplatin-vinorelbine A ELCWP prospective study. Lung Cancer 2013, 82, 340–345. [Google Scholar] [CrossRef] [PubMed]
  342. Boeri, M.; Milione, M.; Proto, C.; Signorelli, D.; Lo Russo, G.; Galeone, C.; Verri, C.; Mensah, M.; Centonze, G.; Martinetti, A.; et al. Circulating microRNAs and PD-L1 tumor expression are associated with survival in advanced NSCLC patients treated with immunotherapy: A prospective study. Clin. Cancer Res. 2019. [Google Scholar] [CrossRef] [PubMed]
  343. Portnoy, V.; Lin, S.H.; Li, K.H.; Burlingame, A.; Hu, Z.H.; Li, H.; Li, L.C. saRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription. Cell Res. 2016, 26, 320–335. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  344. Krutzfeldt, J.; Rajewsky, N.; Braich, R.; Rajeev, K.G.; Tuschl, T.; Manoharan, M.; Stoffel, M. Silencing of microRNAs in vivo with ‘antagomirs’. Nature 2005, 438, 685–689. [Google Scholar] [CrossRef] [PubMed]
  345. Elmen, J.; Lindow, M.; Silahtaroglu, A.; Bak, M.; Christensen, M.; Lind-Thomsen, A.; Hedtjarn, M.; Hansen, J.B.; Hansen, H.F.; Straarup, E.M.; et al. Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver. Nucleic Acids Res. 2008, 36, 1153–1162. [Google Scholar] [CrossRef] [PubMed]
  346. Garzon, R.; Marcucci, G.; Croce, C.M. Targeting microRNAs in cancer: Rationale, strategies and challenges. Nat. Rev. Drug Discov. 2010, 9, 775–789. [Google Scholar] [CrossRef] [PubMed]
  347. Hutvagner, G.; Zamore, P.D. A microRNA in a multiple-turnover RNAi enzyme complex. Science 2002, 297, 2056–2060. [Google Scholar] [CrossRef] [PubMed]
  348. Kota, J.; Chivukula, R.R.; O’Donnell, K.A.; Wentzel, E.A.; Montgomery, C.L.; Hwang, H.W.; Chang, T.C.; Vivekanandan, P.; Torbenson, M.; Clark, K.R.; et al. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 2009, 137, 1005–1017. [Google Scholar] [CrossRef] [PubMed]
  349. Gumireddy, K.; Young, D.D.; Xiong, X.; Hogenesch, J.B.; Huang, Q.; Deiters, A. Small-molecule inhibitors of microrna miR-21 function. Angew. Chem. Int. Ed. Engl. 2008, 47, 7482–7484. [Google Scholar] [CrossRef] [PubMed]
  350. Bakhshandeh, B.; Soleimani, M.; Hafizi, M.; Ghaemi, N. A comparative study on nonviral genetic modifications in cord blood and bone marrow mesenchymal stem cells. Cytotechnology 2012, 64, 523–540. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  351. Yin, H.; Kanasty, R.L.; Eltoukhy, A.A.; Vegas, A.J.; Dorkin, J.R.; Anderson, D.G. Non-viral vectors for gene-based therapy. Nat. Rev. Genet. 2014, 15, 541–555. [Google Scholar] [CrossRef] [PubMed]
  352. Ma, L.; Reinhardt, F.; Pan, E.; Soutschek, J.; Bhat, B.; Marcusson, E.G.; Teruya-Feldstein, J.; Bell, G.W.; Weinberg, R.A. Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model. Nat. Biotechnol. 2010, 28, 341–347. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  353. Tazawa, H.; Tsuchiya, N.; Izumiya, M.; Nakagama, H. Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc. Natl. Acad. Sci. USA 2007, 104, 15472–15477. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  354. Chen, Y.; Zhu, X.; Zhang, X.; Liu, B.; Huang, L. Nanoparticles modified with tumor-targeting scFv deliver siRNA and miRNA for cancer therapy. Mol. Ther. 2010, 18, 1650–1656. [Google Scholar] [CrossRef] [PubMed]
  355. Trang, P.; Medina, P.P.; Wiggins, J.F.; Ruffino, L.; Kelnar, K.; Omotola, M.; Homer, R.; Brown, D.; Bader, A.G.; Weidhaas, J.B.; et al. Regression of murine lung tumors by the let-7 microRNA. Oncogene 2010, 29, 1580–1587. [Google Scholar] [CrossRef] [PubMed]
  356. Wiggins, J.F.; Ruffino, L.; Kelnar, K.; Omotola, M.; Patrawala, L.; Brown, D.; Bader, A.G. Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Res. 2010, 70, 5923–5930. [Google Scholar] [CrossRef] [PubMed]
  357. Stahlhut, C.; Slack, F.J. Combinatorial Action of MicroRNAs let-7 and miR-34 Effectively Synergizes with Erlotinib to Suppress Non-small Cell Lung Cancer Cell Proliferation. Cell Cycle 2015, 14, 2171–2180. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  358. Sun, Y.; Bai, Y.; Zhang, F.; Wang, Y.; Guo, Y.; Guo, L. miR-126 inhibits non-small cell lung cancer cells proliferation by targeting EGFL7. Biochem. Biophys. Res. Commun. 2010, 391, 1483–1489. [Google Scholar] [CrossRef] [PubMed]
  359. Chen, Z.; Zeng, H.; Guo, Y.; Liu, P.; Pan, H.; Deng, A.; Hu, J. miRNA-145 inhibits non-small cell lung cancer cell proliferation by targeting c-Myc. J. Exp. Clin. Cancer Res. 2010, 29, 151. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  360. Chiou, G.Y.; Cherng, J.Y.; Hsu, H.S.; Wang, M.L.; Tsai, C.M.; Lu, K.H.; Chien, Y.; Hung, S.C.; Chen, Y.W.; Wong, C.I.; et al. Cationic polyurethanes-short branch PEI-mediated delivery of Mir145 inhibited epithelial-mesenchymal transdifferentiation and cancer stem-like properties and in lung adenocarcinoma. J. Control. Release 2012, 159, 240–250. [Google Scholar] [CrossRef] [PubMed]
  361. Wu, Y.; Crawford, M.; Yu, B.; Mao, Y.; Nana-Sinkam, S.P.; Lee, L.J. MicroRNA delivery by cationic lipoplexes for lung cancer therapy. Mol. Pharm. 2011, 8, 1381–1389. [Google Scholar] [CrossRef] [PubMed]
  362. Wu, Y.; Crawford, M.; Mao, Y.; Lee, R.J.; Davis, I.C.; Elton, T.S.; Lee, L.J.; Nana-Sinkam, S.P. Therapeutic Delivery of MicroRNA-29b by Cationic Lipoplexes for Lung Cancer. Mol. Ther. Nucleic Acids 2013, 2, e84. [Google Scholar] [CrossRef] [PubMed]
  363. Bouchie, A. First microRNA mimic enters clinic. Nat. Biotechnol. 2013, 31, 577. [Google Scholar] [CrossRef] [PubMed]
  364. Beg, M.S.; Brenner, A.J.; Sachdev, J.; Borad, M.; Kang, Y.K.; Stoudemire, J.; Smith, S.; Bader, A.G.; Kim, S.; Hong, D.S. Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors. Investig. New Drugs 2017, 35, 180–188. [Google Scholar] [CrossRef] [PubMed]
  365. Zhao, J.; Bader, A.G. Evaluating Synergistic Effects of miR-34a Mimics in Combination with Other Therapeutic Agents in Cultured Non-Small Cell Lung Cancer Cells. Methods Mol. Biol. 2017, 1517, 115–126. [Google Scholar] [CrossRef] [PubMed]
  366. Van Zandwijk, N.; Pavlakis, N.; Kao, S.C.; Linton, A.; Boyer, M.J.; Clarke, S.; Huynh, Y.; Chrzanowska, A.; Fulham, M.J.; Bailey, D.L.; et al. Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: A first-in-man, phase 1, open-label, dose-escalation study. Lancet Oncol 2017, 18, 1386–1396. [Google Scholar] [CrossRef]
  367. Reid, G.; Kao, S.C.; Pavlakis, N.; Brahmbhatt, H.; MacDiarmid, J.; Clarke, S.; Boyer, M.; van Zandwijk, N. Clinical development of TargomiRs, a miRNA mimic-based treatment for patients with recurrent thoracic cancer. Epigenomics 2016, 8, 1079–1085. [Google Scholar] [CrossRef] [PubMed]
  368. Fabian, M.R.; Sonenberg, N.; Filipowicz, W. Regulation of mRNA translation and stability by microRNAs. Annu. Rev. Biochem. 2010, 79, 351–379. [Google Scholar] [CrossRef] [PubMed]
  369. Levin, A.A. Treating Disease at the RNA Level with Oligonucleotides. N. Engl. J. Med. 2019, 380, 57–70. [Google Scholar] [CrossRef] [PubMed]
  370. Zhang, Z.P.; Wang, Z.; Liu, X.Y.; Sun, Z.G.; Cheng, G.; Yu, Y. Inhibition effect of up-regulation of p21~(WAF1/CIP1) by small activating RNA on cell proliferation and promotes apoptosis in lung cancer cells. Chin. J. Cancer Prev. Treat. 2011, 14, 1080–1083. [Google Scholar]
  371. Wei, J.; Zhao, J.; Long, M.; Han, Y.; Wang, X.; Lin, F.; Ren, J.; He, T.; Zhang, H. p21WAF1/CIP1 gene transcriptional activation exerts cell growth inhibition and enhances chemosensitivity to cisplatin in lung carcinoma cell. BMC Cancer 2010, 10, 632. [Google Scholar] [CrossRef] [PubMed]
  372. Zheng, L.; Wang, L.; Gan, J.; Zhang, H. RNA activation: Promise as a new weapon against cancer. Cancer Lett. 2014, 355, 18–24. [Google Scholar] [CrossRef] [PubMed]
  373. Li, Q.J.; Chau, J.; Ebert, P.J.; Sylvester, G.; Min, H.; Liu, G.; Braich, R.; Manoharan, M.; Soutschek, J.; Skare, P.; et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 2007, 129, 147–161. [Google Scholar] [CrossRef] [PubMed]
  374. Aagaard, L.; Rossi, J.J. RNAi therapeutics: Principles, prospects and challenges. Adv. Drug Deliv. Rev. 2007, 59, 75–86. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  375. Zhao, X.; Pan, F.; Holt, C.M.; Lewis, A.L.; Lu, J.R. Controlled delivery of antisense oligonucleotides: A brief review of current strategies. Expert Opin. Drug Deliv. 2009, 6, 673–686. [Google Scholar] [CrossRef] [PubMed]
  376. Grimm, D.; Streetz, K.L.; Jopling, C.L.; Storm, T.A.; Pandey, K.; Davis, C.R.; Marion, P.; Salazar, F.; Kay, M.A. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 2006, 441, 537–541. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. MicroRNAs involved in distinct steps of metastasis including EMT and migration/invasion in lung cancer. EMT: epithelial-to-mesenchymal transition; MET: mesenchymal-to-epithelial transition.
Figure 1. MicroRNAs involved in distinct steps of metastasis including EMT and migration/invasion in lung cancer. EMT: epithelial-to-mesenchymal transition; MET: mesenchymal-to-epithelial transition.
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Cancers 11 00265 g002 550
Figure 2. MiRNA expression profiling in NSCLC associated with brain, bone, and lymph node metastasis.
Figure 2. MiRNA expression profiling in NSCLC associated with brain, bone, and lymph node metastasis.
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Table
Table 1. Epithelial-to-mesenchymal transition-related transcription factors and associated microRNAs in Non-Small Cell Lung Cancer (NSCLC).
Table 1. Epithelial-to-mesenchymal transition-related transcription factors and associated microRNAs in Non-Small Cell Lung Cancer (NSCLC).
Epithelial-to-Mesenchymal Transition-Related Transcription Factors
SnailSlugZEB1ZEB2TwistOther (miRNA/Related Gene or Target)
miR-22 [36]miR-1 [40]miR-33b [41]miR-132 [42]miR-33a [43]miR-19/PTEN [44]miR-204/SIX1 [45]
miR-30 [37,38]miR-124 [46,47]miR-34a [48]miR-138 [49]miR-92b [50]miR-21/Pdcd4 [51]miR-205-5p/Integrin α5 [52]
miR-34 [33]miR-137 [53]miR-101 [54]miR-145 [55]miR-98 [56]miR-26a/PTEN [57]miR-205-5p/Smad4 [58]
miR-126 [34]miR-218 [59]miR-124 [60]miR-154 [61]miR-381 [39]miR-105/Mcl-1 [62]miR-206/MET [63]
miR-346 [35]miR-452 [64]miR-144 [65,66]miR-155-5p [67] miR-124/STAT3 [68]miR-221&222/PTEN, TIMP3 [69]
miR-381 [39] miR-155-5p [67]miR-200c [70] miR-133/FOXQ1 [71]miR-302b-3p/GCNT3 [72]
miR-181 [73]miR-205-5p [74] miR-135b/LZTS1, Hippo pathway [75]miR-361-3p/SH2B1 [76]
miR-199b [77]miR-203 [78] miR-136/Smad2/3 [79]miR-455-5p/SOCO3 [80]
miR-200s [81,82]miR-215 [83] miR-145/N-cadherin [84]miR-489/SUL12 [85]
miR-205-5p [74]miR-218 [59] miR-145/MTDH [86]miR-497/MTDH [86]
miR-216a [87]miR-338-3p [88] miR-148a/ROCK1 [89]miR-544a/cadherina 1 [90]
miR-455-3p [91]miR-598 [92] miR-148b/ROCK1 [93]miR-590-3p/OLFM4 [94]
miR-1199-5p [95] miR-150/FOXO4 [96]miR-590-5p/ADAM9 [97]
miR-155-5p/Smad2/3 [67]miR-590-5p/GAB1 [98]
miR-183/MTA1 [99]miR-598/Derlin 1 [100]
miR-191/HIF-2α [101]miR-664/AKT [102]
miR-195/MYB [103]miR-876-5p/BMP-4 [104]
miR-196a/HOXA5 [105]miR-1260b/PTPRK [106]
PTEN: phosphatase and tensin homolog; PDCD4: programmed cell death protein 4; TWIST1: twist family BHLH transcription factor 1; Mcl-1: myeloid cell leukemia 1; STAT3: signal transducer and activator of transcription 3; FOXQ1: forkhead box protein Q1; MTDH: metadherin; ROCK1: Rho-associated coiled-coil containing protein kinase; FOXO4: forkhead box protein O4; MTA1: metastasis-associated protein 1; HIF-2α: hypoxia-inducible factor 2-alpha; MYB: myeloblastosis; HOXA5: homeobox A5; SIX1: sineoculis homeobox homolog 1; MET: hepatocyte growth factor receptor; TIMP3: tissue inhibitor of metalloproteinase 3; GCNT3: glucosaminyl (N-acetyl) transferase 3, mucin type; SH2B1: Src homology 2B (SH2B) family member 1; SOCO3: suppressor of cytokine signaling 3; SUL12: polycomb repressive complex 2 subunit; OLFM4: olfactomedin 4; ADAM9: a disintegrin and metalloproteinase 9; GAB1: Grb2-associated binder 1; AKT: protein kinase B; BMP-4: bone morphogenetic protein 4; PTPRK: protein tyrosine phosphatase, receptor type K.
Table
Table 2. Bone metastasis-related miRNAs in NSCLC.
Table 2. Bone metastasis-related miRNAs in NSCLC.
miRNADirect or Related TargetTumor Suppressor/OncogeneTissueEffectAuthor/Reference
miR-21COX19OncogeneMetastatic bone tissuePromoted cell proliferation, inhibited apoptosisGuo et al. [149]
miR-21PDCD4OncogeneTCGA databasePromoted osteoclastogenesis and tumorigenesis. High miR-21 correlated with poor prognosis according to TCGA database.Xu et al. [152]
Hsv2-miR-H9-5pSOCS2OncogeneLung tumorsIncreased cell survival, migration, and invasionWang et al. [155]
miR-33aPTHrPSuppressorLung cancer cell lines (A549, H1299, and BEAS-2B)Reduced the stimulatory effect of A549 on the production of osteoclastogenesis activator RANKL and M-CSF on osteoblasts, and increased the production of osteoprotegerin.Kuo et al. [158]
miR-139-5pNotch1SuppressorSerumMiR-139-5p expression was increased during MSC differentiation toward osteoblasts and positively regulated osteogenic differentiation.Xu et al. [159]
miR-192ICAM-1 and PTPRJSuppressorIn vivo (mice)Decreased tumor-induced angiogenesisValencia et al. [160]
miR-203TGF-β/SMAD2SuppressorTumor tissuesSuppressed cell proliferation and migration, induced apoptosis; repressed TGF-β/Smad2Wei et al. [161]
COX19: cytochrome C oxidase assembly homolog 19; PDCD4: programmed cell death 4; SOCS2: suppressor of cytokine signaling 2; PTHrP: parathyroid hormone-related protein; Notch1: Notch homolog 1, translocation-associated (Drosophila); RANKL: receptor activator of nuclear factor κ-B ligand; M-CSF: macrophage colony-stimulating factor; MSC: mesenchymal stem cell.
Table
Table 3. Brain metastasis-related microRNAs in NSCLC.
Table 3. Brain metastasis-related microRNAs in NSCLC.
miRNADirect or Related TargetTumor Suppressor/OncogeneTissueEffectAuthor/Reference
miR-21SPRY2, TIMP3, CDKN1A, SERPINB5 and PTEN.OncogeneIn vivoPromoted brain metastasis-initiating cell (BMIC) self-renewal and proliferation.Singh et al. [166]
miR-95-3pCyclin D1SuppressorIn vivoInhibited cell invasion, proliferation, and colony formation.Hwang et al. [167]
miR-145 SuppressorBrain and lung tumorsInhibited cell proliferationZhao et al. [163]
miR-145-5pTPD52SuppressorBrain and lung tumorsInhibited cell invasion and migration. Restrained brain orthotopic tumor engraftment in vivo.Donzelli et al. [165]
miR-142-3pTRPA1SuppressorTCGA dataSuppressed NSCLC progressionBerrout et al. [168]
miR-184, miR-197 EGFR-mutant lung tumors Remon et al. [169]
miR-15a, miR-210, miR-214 Lung tumorThe Forest model of the three-miRNA signature could be used to predict brain metastasis of lung adenocarcinoma patientsZhao et al. [170]
miR-328PRKCAOncogeneBrain and lung tumorsIncreased cell migration. Up-regulated PRKCAArora et al. [171]
miR-330-3pGRIA3OncogeneLung tumorsPromoted cell growth, invasion, and migration. Up-regulated total DNA methylation. Radiation-resistanceWei et al. [172]
Jiang et al. [173]
miR-375VEGF and MMP-9SuppressorBrain and lung tumors Chen et al. [174]
miR-378MMP-2, MMP-9 and VEGFOncogeneBrain and lung tumorsPromoted cell migration, invasion, and tumor angiogenesis.Chen et al. [175]
miR-423-5pMTSS1OncogeneLung tumorsPromoted NSCLC cell colony formation, cell motility, invasion, and migration.Sun et al. [176]
miR-490-3pPCBP1OncogeneBrain tissuesPromoted cell proliferation, invasion, and migration.Li et al. [177]
miR-590ADAM9SuppressorLung tumorsSuppressed tumorigenesis and invasion.Wang et al. [97]
miR-4317FGF9 and CCND2SuppressorLung tumorsInhibited proliferation, colony formation, migration, and invasion, and hampered cyclingHe et al. [178]
NTSS1: metastasis suppressor 1; TPD52: tumor protein D52; TRPA1: transient receptor potential ankyrin 1; GRIA3: glutamate receptor, ionotropic, AMPA 3; MTSS1: metastasis suppressor protein 1; PCBP1: poly r(C)-binding protein 1; ADAM9: a disintegrin and metalloproteinase 9; FGF9: fibroblast growth factor 9; CCND2: cyclin D2; PRKCA: protein kinase C-α; MMP: matrix metalloprotease; TCGA: The Cancer Genome Atlas.
Table
Table 4. Lymph node metastasis-related microRNAs in NSCLC.
Table 4. Lymph node metastasis-related microRNAs in NSCLC.
miRNADirect or Related TargetTumor Suppressor/OncogeneTissueEffectAuthor/Reference
Let-7gHMGA2, ERCC6 and MAP3K3 *SuppressorLung tumorThe combination of Let-7g and miR-21 profiling and KRAS mutational status may be considered a useful biomarker for clinical management of NSCLC patients.Capodanno et al. [194]
miR-1PIK3CASuppressorLung tumorsLow expression of miR-1 and overexpression of PIK3CA in NSCLC tissues may be useful predictors of lymph node metastasis and postoperative recurrence in patients with NSCLC.Zhao et al. [195]
miR-7Bcl-2SuppressorLung tumorOverexpressed CDR1as in NSCLC functioned to promote tumor progression via miR-7 signals. Up-regulated miR-7 increased the sensitivity of lung adenocarcinoma cells to CDDP by inducing apoptosis.Zhang et al. [196], Cheng et al. [197]
miR-9s OncogeneLung tumorsInvolved in NSCLC progression and could serve as a promising biomarker.Muraoka et al. [198], Xu et al. [199]
miR-10aPTENOncogeneLung tumorsPromoted NSCLC cell proliferation, migration, and invasion.Yu et al. [200]
miR-10bE-cadherinOncogeneLunt tumors PBMCE-cadherin mRNA and protein were overexpressed in miR-10b-suppressed cells compared with controls. MiR-10b expression in PBMCs had predictive value for tumor response to chemotherapy and prognosis for advanced NSCLC patients.Zhang et al. [201], Yang et al. [202], Yang et al. [203], Li et al. [204]
miR-17-5p OncogeneLung tumorsIncreased cell proliferation. LncRNA HNF1A-AS1 promoted cell proliferation and invasion by directly targeting miR-17-5p in NSCLC.Zhang et al. [205]
miR-18a OncogeneLung tumorsCorrelated with stage, lymph node metastasis, and radio-resistance.Shen et al. [206]
miR-19a/b OncogeneLunt tumors, SerumMiR-19b is a potential biomarker for the prediction of survival and response to chemotherapy in NSCLC.Lin et al. [207], Wu et al. [208]
miR-21PTENOncogeneLung tumors, SerumReduced radio-sensitivity in vitro. Promoted cell proliferation and cell cycle progression. High serum level was associated with poor prognosis.Liu et al. [209], Wang et al. [210], Liu et al. [211], Wang et al. [212], Tian et al. [213]
miR-25 OncogeneLung adenocarcinoma tissuesPositive correlation with lymph node metastasis, stage, and EGFR mutations.Xu et al. [214]
miR-26aPTENOncogeneLung tumorsEnhanced lung cancer cell migration and invasion abilities. Up-regulated β-catenin, MMP-2, Twist, and VEGF.Liu et al. [57]
miR-29bMMP2SuppressorLung tumorSuppressed migration and invasion.Wang et al. [215]
miR-30aBCL11ASuppressorLung tumorsA potential diagnostic and prognostic biomarker.Jiang et al. [216]
miR-30bEGFR Cthrc1SuppressorLung tumorsInhibited proliferation, migration, and invasion, induced apoptosis, and enhanced sensitivity of NSCLC cells to EGFR-TKIs.Qi et al. [217], Chen et al. [218]
miR-31CDK5, PTEN, p70S6K, ERK/MAPK, and PI3K/AKT #OncogeneLung tumorsPromoted cell proliferation, invasion, and migration.Meng et al. [219]
miR-32 SuppressorLung tumorsInversely correlated with tumor stage, lymph node metastasis, and OS.Bai et al. [220]
miR-33bZEB1SuppressorLung tumorsInhibited cell growth, invasion, and EMT by suppressing Wnt/β-catenin/ZEB1 signaling.Qu et al. [41]
miR-34a SuppressorLung tumors and plasmaPlasma miR-34a negatively predicted lymph node metastasis. Lower miR-34a was correlated with longer survival.Zhao et al. [221]
miR-92aPTENOncogeneLung tumorsPromoted cell growth, metastasis, and chemo-resistance.Ren et al. [222]
miR-96FOXO3OncogeneLung tumorsPromoted cell invasion and inhibited apoptosis.Li et al. [223]
miR-98 SuppressorSerumLow serum miR-98 was positively correlated with advanced TNM stage, lymph node metastasis, and unfavorable OS.Wang et al. [224]
miR-99amTORSuppressorLung tumorsInversely correlated with lymph node metastasis.Gu et al. [225]
miR-100PLK1SuppressorLung tumorsInhibited cell proliferation and caused G2/M cell cycle arrestLiu et al. [226]
miR-101Mcl-1 ZEB1SuppressorLung tumorsInhibited cell proliferation, invasion, and migration.Luo et al. [227], Han et al. [54]
miR-101-3pSOX9SuppressorLung tumorsLncRNA SNHG1 contributed to the progression of NSCLC through inhibition of miR-101-3p and activation of the Wnt/β-catenin signaling pathway.Lu et al. [228], Cui et al. [229]
miR-106b OncogeneLung tumorOverexpression of miRNA-106b was strongly associated with lymph node metastasis and poor prognosis.Li et al. [230]
miR-107BNDFSuppressorLung tumorsmiR-107 significantly inversely correlated with tumor progression and decreased survival in patients with NSCLC.Zhong et al. [231], Xia et al. [232]
miR-124SOX8, STAT3SuppressorLung tumorsInhibited cell proliferation and induced apoptosis. HOXA11-AS acted as a competing endogenous RNA to regulate transcriptional factor Sp1 expression by sponging miR-124.Xie et al. [233], Li et al. [68], Yu et al. [234]
miR-125a-3pIGF2, CCL4SuppressorLung tumorsSuppressed cell invasion and migration. Inversely correlated with lymph node metastasis.Jiang et al. [235], Hou et al. [236]
miR-125a-5pNEDD9UncertainLung tumorsThe effects on cell invasion and migration and the relationship between miR-125a-5p and lymph node metastasis were controversial in lung cancers.Jiang et al. [235]
Zheng et al. [237]
miR-125bMMP13SuppressorLung tumorsInhibited cell invasion in vitro and in vivo.Yu et al. [238]
miR-126-3p/5p44 co-targets SuppressorLung tumors,Lower expression of miRNA-126-3p and -5p was indicative of vascular invasion, lymph node spread, and an advanced TNM stage of lung adenocarcinoma.Chen et al. [239], Chen et al. [240]
miR-128VEGF-CSuppressorLung tumorsInhibited cell proliferation, colony formation, invasion, and migration.Hu et al. [241]
miR-129-5p SuppressorLung tumorLncRNA NNT-AS1 exerted functions in NSCLC by altering NNT-AS1/miR-129-5p axisShen et al. [242]
miR-130PTENSuppressorLung tumorInhibited NSCLC cell growth and increased cell apoptosis.Ye et al. [243]
miR-130a OncogeneLung tumorOverexpressed in NSCLC tissue and correlated with lymph node spreading.Wang et al. [244]
miR-132ZEB2SuppressorLung tumorInhibited cell proliferation, invasion, and migration, and decreased apoptosisYou et al. [42]
miR-133a-3p SuppressorLung tumor (TCGA)Associated with longer survival time and negative lymph node metastasis.Yang et al. [245]
miR-133bEGFRSuppressorLung tumorInhibited cell invasion, induced apoptosis, and enhanced sensitivity to gefitinib. HOXD-AS1 directly targeted miR-133b to promote cell migration and invasion.Liu et al. [246], Xia et al. [247], Chen et al. [240]
miR-138PDK1, Sirt1, YAP1SuppressorLung tumorInversely correlated with lymph node metastasisHan et al. [248], Ye et al. [249], Xiao et al. [250]
miR-139PDE2ASuppressorLung tumorH3K27me3-mediated down-regulation of miR-139. Enhanced invasive and metastasis ability of NSCLC cells.Watanabe et al. [251]
miR-141 OncogeneLung tumorPositively associated with tumor size and, lymph node metastasis.Zhang et al. [252]
miR-145AEG-1/MTDH RIOK2, NOB1 N-cadherinSuppressorLung tumorsInhibited cell invasion and migrationWang et al. [253], Liu et al. [254], Gan et al. [255], Mo et al. [84], Li et al. [204]
miR-146a SuppressorSerumLower serum level in NSCLC patients.Wu et al. [208]
miR-147 SuppressorLung tumor, SerumLow serum miR-147 expression level was correlated with lymph node metastasis and worse OS.Chu et al. [256]
miR-148aROCK1 Wnt1SuppressorLung tumorsReduced cell invasion and inhibited EMTLi et al. [89], Chen et al. [257], Chen et al. [258], Li et al. [259]
miR-148b SuppressorLung tumorsHigh miR-148b expression had a favorable prognosis.Ge et al. [260]
miR-150 OncogeneLung tumorsHigh miR-150 expression had a poor prognosis.Yin et al. [261]
miR-153ADAM19SuppressorLung tumorsInhibited cell proliferation, migration, and invasion.Shan et al. [262], Chen et al. [263]
miR-181a-5pHMGB2SuppressorLung tumorsLncRNA NEAT1 promoted proliferation and invasion by targeting miR-181a-5p.Li et al. [264]
miR-181b SuppressorLung tumorsLncRNA NEAT1 up-regulated the miR-181a-5p-targeted gene HMGB2 through acting as a competitive "sponge" of miR-181a-5p.Yang et al. [265]
miR-183-3p OncogeneLung adenocarcinoma tissuesInvolved in lung cancer pathogenesis and progression, and could be used as a potential prognostic biomarker of female lung adenocarcinoma.Xu et al. [266]
miR-185KLF7SuppressorLung tumorsInhibited the cell propagation, cell colony formation, and incursion capacities in vitro.Zhao et al. [267]
miR-186Cdc42SuppressorLung tumorsInhibited cell invasion and metastasisDong et al. [268], Li et al. [269]
miR-193a-3pERBB4, S6K2 AEG-1SuppressorLung tumorsInhibited NSCLC cell migration, invasion, and EMT in vitro and lung metastasis formation in vivo.Yu et al. [270], Ren et al. [271]
miR-193a-5pPIK3R3 mTORSuppressorLung tumorsInhibited NSCLC cell migration, invasion, and EMT in vitro and lung metastasis formation in vivo.Yu et al. [272]
miR-195 SuppressorPlasmaDecreased plasma miRNA-195 expression was associated with lymph node metastasis and advanced clinical stageSu et al. [273]
miR-198SHMT1SuppressorLung adenocarcinomaInhibited cell proliferation, enhanced cell apoptosis, and led to cell-cycle arrestWu et al. [274]
miR-200cUSP25SuppressorLung tumorsInhibited cell invasion and migration. Negatively correlated with lymph node metastasis.Li et al. [115], Ceppi et al. [275]
miR-200c OncogeneLung tumorHigher expression of miR-200c was associated with poor prognosis.Si et al. [276], Liu et al. [209]
miR-202STAT3SuppressorLung tumorsInhibited cell proliferation, migration, and invasion.Zhao et al. [277]
miR-203LASP-1SuppressorLung tumorsLASP-1, regulated by miR-203, promoted tumor proliferation and aggressiveness in human NSCLC.Zheng et al. [278]
miR-210 OncogeneLung tumor SerumMiR-210 expression levels might be a novel diagnostic and prognostic marker of NSCLCOsugi et al. [279], Li et al. [280]
miR-211-3p SuppressorLung tumorsLncRNA SNHG15 promoted cell proliferation and migration by targeting miR-211-3pCui et al. [281]
miR-212SOX4SuppressorLung tumorsSuppressed cell migration and invasion, and EMT in NSCLC cellsTang et al. [282]
miR-215ZEB2SuppressorLung tumorsInhibited cell migration and invasion.Hou et al. [83]
miR-218Slug/ZEB2SuppressorLung tumorsInhibited cell migration and invasion.Shi et al. [59]
miR-221 OncogeneLung tumorsCorrelated with lymph node metastasis and disease progression.Zhang et al. [283]
miR-224 SuppressorLung tumorsInhibited cell proliferation, invasion, and migration, and promoted cell apoptosis.Zhu et al. [284]
miR-301a OncogeneLung tumorsmiR-301a overexpression was correlated with lymph node metastasis and poor prognosis.Shi et al. [285]
miR-302b-3pGCNT3SuppressorLung tumorsInhibited proliferation, migration, and invasionLi et al. [72]
miR-328-3pγ-H2AXSuppressorLung tumorsUp-regulated miR-328-3p demonstrated a survival inhibition effect in A549 and restored NSCLC cell sensitivity to radiotherapy.Ma et al. [286]
miR-335Bcl-w, SP1SuppressorLung tumorsInhibited cell proliferation, migration, Increased apoptosis.Wang et al. [287]
miR-338-3pIRS2SuppressorLung tumorsInhibited growth and invasion.Zhang et al. [288]
miR-339-5pBCL6SuppressorLung tumors, Peripheral bloodInhibited cell migration and invasionLi et al. [289], Li et al. [290]
miR-340CDK4SuppressorLung tumorsSuppressed cell proliferation.Qin et al. [291]
miR-361-3pSH2B1SuppressorLung tumorsInhibited cell growth, proliferation, colony formation, invasion, and migrationChen et al. [76]
miR-361-5p SuppressorLung tumorsLower miR-361-5p expression was found in NSCLC and associated lymph node metastasis.Zhuang et al. [292]
miR-365TTF-1SuppressorSerumHigh miR-365 serum level had less lymph node metastasis and longer OS.Liu et al. [293], Sun et al. [294]
miR-378HMOX1OncogeneLung tumorsModulated NSCLC progression and angiogenesisSkrzypek et al. [295]
Mir-379IGF-1RSuppressorLung tumorsInhibited cell proliferation, migration, and invasion.Zhou et al. [296]
miR-381LRH-1SuppressorLung tumorsInhibited cell migration and invasion in vitro and in vivo.Tian et al. [297]
miR-383 SuppressorLung tumorsReduced proliferation, invasion, and migration.Shang et al. [298]
miR-409-3pc-METSuppressorLung adenocarcinoma tumorsInhibited cell proliferation, induced apoptosis, and reduced invasion and migration by silencing of AKT signaling.Wan et al. [299]
miR-411 OncogeneSerumElevated serum miR-411 expression was correlated with lymph node metastasis and poor prognosis.Wang et al. [300]
miR-421 OncogeneLung tumors, SerumPromoted cell proliferation, invasion, and migration.Li et al. [301]
miR-422a61 potential target genes §OncogeneLymph nodes and plasmaHigh expression in NSCLC metastatic lymph nodes and validated by fresh blood of patients.Wu et al. [302]
miR-433E2F3SuppressorLung tumorsReduced cell proliferation and invasionLiu et al. [303]
miR-448DCLK1SuppressorLung squamous cell carcinomaInhibited cell proliferation, colony formation, migration, and invasionShan et al. [304]
miR-449ac-METSuppressorLung tumorsInhibited cell migration and invasionLuo et al. [305]
miR-451RAB14SuppressorLung tumors,Inhibited cell proliferation and triggered apoptosisWang et al. [306], Wang et al. [307]
miR-451a OncogenePlasmaExosomal miR-451a showed a significant association with lymph node metastasis, vascular invasion, and stageKanaoka et al. [308]
miR-452BMI1SuppressorLung tumorsInhibited cell invasion, but not cell proliferation or apoptosis.He et al. [309]
miR-452-5p10 hub genes@SuppressorLung tumors, TCGALow miR-452-5p expression level played an essential role in lung adenocarcinoma.Gan et al. [310]
miR-454PTENOncogeneLung tumorsPromoted cell proliferation, invasion, and migration and inhibited apoptosis.Zhu et al. [311]
miR-485-5pIGF2BP2SuppressorLung tumorsInhibited cell growth, invasion, and caused G0/G1 arrestHuang et al. [312]
miR-486-5pARHGAP5, Pim-1SuppressorLung tumors, Sputum, plasmaInhibited tumor progression and metastasisShen et al. [313], Wang et al. [314], Pang et al. [315]
miR-490-3pPCBP1OncogeneLung tumorsPromoted cell proliferation, invasion, and migration.Li et al. [177]
miR-491-5pIGF2BP1SuppressorLung tumorsReduced cell proliferation, colony formation, migration, and invasionGong et al. [316]
miR-494 OncogeneLung tumor, SerumHigh miR-494 level was correlated with lymph node metastasis and poor prognosis.Zhang et al. [317], Wang et al. [318]
miR-504LOXL2SuppressorLung tumorsInhibited cell proliferation, cell invasion, and EMT process of NSCLCYe et al. [319]
miR-506-3pCOTL1SuppressorLung tumorsReduced cell growth, migration, and invasion in vitro and in vivo.Guo et al. [320]
miR-520bRad22ASuppressorLung tumorsInhibited cell proliferation, invasion, and metastasis abilitiesZhang et al. [321]
miR-548IAKT1SuppressorLung tumorsInhibited NSCLC cell migration and invasion.Liu et al. [322]
miR-582-5pMAP3K2SuppressorLung tumorsSuppressed the proliferation, migration, and invasion of NSCLC cellsWang et al. [323]
miR-588GRNSuppressorLung squamous cell carcinomaSuppressed tumor cell migration and invasion.Qian et al. [324]
miR-590OLFM4OncogeneLung adenocarcinomaPromoted cell migration and invasion.Liu et al. [94]
miR-592SOX9SuppressorLung tumorsReduced cell proliferation, colony formation, migration, and invasion.Li et al. [325]
miR-598ZEB2SuppressorLung tumorsReduced NSCLC cell proliferation and invasion.Tong et al. [92]
miR-638 SuppressorSerumSerum miR-638 expression levels in NSCLC patients after chemotherapy were associated with disease prognosis.Wang et al. [326]
miR-650ING4OncogeneLung tumorsInhibited caspase-3-dependent apoptosisHuang et al. [327]
miR652-3pLgl1OncogeneLung tumorsPromoted cell proliferation, invasion, and migration.Yang et al. [328]
miR-661RUNX3OncogeneLung tumorsDown-regulation of miR-661 suppressed NSCLC proliferation and invasion.Wang et al. [329]
miR-675-5pGPR55SuppressorLung tumorsInhibited cell proliferation, colony formation, invasion, and migration, and attenuated the tumorigenicity in vivo.He et al. [330]
miR-874MMP2, XIAPSuppressorLung tumorsLncRNA XLOC_008466 functioned as an oncogene in NSCLC by regulating the miR-874-MMP2/XIAP axisYang et al. [331]
miR-935E2F7SuppressorLung tumorsSuppressed cell proliferation, migration, and invasionWang et al. [332]
miR-1204PITX1OncogeneLung tumorsPromoted cell proliferation and reduced cell cycle arrest.Jiang et al. [333]
miR-1269TP53, Caspase-9OncogeneLung tumors, TCGAPromoted cell survival and proliferation.Bao et al. [334]
miR-1290IRF2OncogeneLung tumors SerumPromoted cell growthJin et al. [335], Mo. Et al. [336]
miR-4317FGF9 CCND2SuppressorLung tumorsInhibited proliferation, colony formation, migration, and invasion, and hampered cyclesHe et al. [178]
miR-6754-5p SuppressorLung tumorsLncRNA LINC00978 promoted cell proliferation and invasion in NSCLC by inhibiting miR-6754-5p.Li et al. [337]
* There were 24 putative target genes for Let-7g after analysis by miRanda, TargetScan, Pictar and miRDB prediction algorithms. # TargetScan software were applied for in silico prediction of miR-31 targets. There were 44 co-regulated target genes of both miRNA-126-3p and miRNA-126-5p by using twelve target gene prediction software programs (TargetScan, miRWalk, Microt4, miRDB, miRanda, miRBridge, miRMap, miRNAMap, PITA, PicTar2, RNA22 and RNAhybrid). § Identified by predicting by online database, miRecords and mining of the data from Gene Expression Omnibus (GEO) and TCGA. @ Total of the fourteen prediction programs were used for screened the putative target genes. STRING database was used for the selection of hub genes which were probably involved in the strategic pathway related to lung adenocarcinoma. Bcl-2: B-cell lymphoma 2; PTEN: phosphatase and tensin homolog; PBMC: peripheral blood mononuclear cell; BCL11A: B-cell lymphoma/leukemia 11A; Cthrc1: collagen triple helix repeat containing 1; PLK-1: polo-like kinase 1; Mcl-1: myeloid cell leukemia 1; lncRNA SNHG1: long non-coding RNA small nucleolar RNA host gene 1; BDNF: brain-derived neurotrophic factor; NEDD9: neural precursor cell expressed, developmentally down-regulated 9; PDK1: 3-phosphoinositide-dependent protein kinase-1; Sirt1: silent mating type information regulation 2 homolog 1; YAP1: Yes associated protein 1; AEG-1: astrocyte elevated gene-1; MTDH: metadherin; RIOK2: right open reading frame kinase 2; NOB1: nin one binding protein; KLF7: Kruppel-like factor 7; PTTG1: pituitary tumor-transforming 1; Cdc42: cell division control protein 42 homolog; ERBB4: erb-b2 receptor tyrosine kinase 4; S6K2: S6 kinase 2; PIK3R3: phosphatidylinositol 3-kinase, regulatory subunit 3; mTOR: mammalian target of rapamycin; SHMT1: serine hydroxymethyltransferase 1; USP25: ubiquitin-specific protease 25; LASP-1: LIM and SH3 protein 1; GCNT3: glucosaminyl (N-acetyl) transferase 3, mucin type; γ-H2AX: phosphorylated histone H2AX; Bcl-w: B-cell lymphoma 2 like 2; SP1: specificity protein 1; IRS2: insulin receptor substrate 2; Bcl-6: B-cell lymphoma 6; CDK4: cyclin-dependent kinase 4; SH2B1: Src homology 2B (SH2B) family members 1; HMOX1: heme oxygenase-1; IGF-1R: insulin-like growth factor 1 receptor; LRH-1: liver receptor homolog-1; E2F3: human E2F transcription factor 3; DCLK1: doublecortin-like kinase 1; c-MET: hepatocyte growth factor receptor; RAB14: ras-related protein 14; BMI1: B lymphoma Mo-MLV insertion region 1; IGF2BP2: insulin-like growth factor 2 mRNA-binding protein 2; ARHGAP5: Rho GTPase-activating protein 5; Pim-1: proviral integration site 1; PCBP1: poly(RC) binding protein 1; IGF2BP1: insulin-like growth factor 2 mRNA-binding protein 1; LOXL2: lysyl oxidase-like 2; COTL1: coactosin-like protein; Rad22A: DNA repair and recombination protein rad22; PDE2A: Phosphodiesterase 2A; MAP3K2: mitogen-activated protein kinase kinase kinase 2; GRN: progranulin; OLFM4: olfactomedin 4; ING4: inhibitor of growth 4; Lgl1: late gestation lung protein 1; RUNX3: runt-related transcription factor 3; GPR55: G protein-coupled receptor 55; XIAP: X-linked inhibitor of apoptosis protein; E2F7: Homo sapiens E2F transcription factor 7; PITX1: paired like homeodomain 1; TP53: tumor protein p53; IRF2: interferon regulatory factor 2; FGF9: fibroblast growth factor 9; CCND2: cyclin D2.
Table
Table 5. MicroRNA-targeted therapy for lung cancer.
Table 5. MicroRNA-targeted therapy for lung cancer.
Phase of Drug DevelopmentYearmiRNATargetDelivery SystemAuthor/Reference
In vitro2010miR-145C-MYCLentivirusChen et al. [359]
In vitro, In vivo2012miR-145OCT4, SOX2PolyethyleniminesChiou et al. [360]
In vitro, In vivo2010miR-126EGFL7LipidSun et al. [358]
In vitro, In vivo2010Let-7KRASLentivirusTrang et al. [355]
In vitro, In vivo2010, 2011miR-34aBCL-2Neutral lipidWiggins et al. [356], Trang et al. [272]
In vitro, In vivo2011, 2015Let-7, miR-34aKRAS, TP53Lentivirus, LipidTrang et al. [272], Stahlhut et al. [357]
In vitro, In vivo2011miR-133bMCL-1Cationic lipoplexWu et al. [361]
In vitro, In vivo2013miR-29bMCL-1, CDK6, DNMT3LipidWu et al. [362]
Phase I (NCT01829971)Start: 2013 Termination: 2016miR-34aBCL-2Lipid
Phase I (NCT02369198)2017miR-16EGFRBacterial minicellsvan Zandwijk et al. [366]
Oct4: octamer-binding transcription factor 4, Sox2: sex determining region Y-box 2; EGFL7: epidermal growth factor–like domain 7; KRAS: Kirsten rat sarcoma 2 viral oncogene homolog; Bcl-2: B-cell lymphoma 2; TP53: tumor protein P53, Mcl-1: myeloid cell leukemia 1; CDK6: cell division protein kinase 6; DNMT3: DNA methyltransferase 3; EGFR: epidermal growth factor receptor.

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Wu, S.-G.; Chang, T.-H.; Liu, Y.-N.; Shih, J.-Y. MicroRNA in Lung Cancer Metastasis. Cancers 2019, 11, 265. https://doi.org/10.3390/cancers11020265

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Wu S-G, Chang T-H, Liu Y-N, Shih J-Y. MicroRNA in Lung Cancer Metastasis. Cancers. 2019; 11(2):265. https://doi.org/10.3390/cancers11020265

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Wu, Shang-Gin, Tzu-Hua Chang, Yi-Nan Liu, and Jin-Yuan Shih. 2019. "MicroRNA in Lung Cancer Metastasis" Cancers 11, no. 2: 265. https://doi.org/10.3390/cancers11020265

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