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Review

MicroRNA in Papillary Thyroid Carcinoma: A Systematic Review from 2018 to June 2020

1
Doctoral School, Iuliu Hațieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
2
Department of Medical Oncology, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
3
Department of Dermatology, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
4
Radiology and Imaging Department, County Emergency Hospital, Cluj-Napoca, Clinicilor Street, Number 3-5, Cluj-Napoca, 400006 Cluj, Romania
5
Department of Endocrine Tumors and Nuclear Medicine, Institute of Oncology “Prof.dr.Ion Chiricut,ă” 400015 Cluj-Napoca, Romania
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(11), 3118; https://doi.org/10.3390/cancers12113118
Submission received: 9 September 2020 / Revised: 19 October 2020 / Accepted: 21 October 2020 / Published: 25 October 2020
(This article belongs to the Special Issue Nucleic Acids in Cancer Diagnosis and Therapy)

Abstract

:

Simple Summary

The most common form of endocrine cancer - papillary thyroid carcinoma, has an increasing incidence. Although this disease usually has an indolent behavior, there are cases when it can evolve more aggressively. It has been known for some time that it is possible to use microRNAs for the diagnosis, prognosis and even treatment monitoring of papillary thyroid cancer. The purpose of this study is to summarize the latest information provided by publications regarding the involvement of microRNAs in papillary thyroid cancer, underling the new clinical perspectives offered by these publications.

Abstract

The involvement of micro-ribonucleic acid (microRNAs) in metabolic pathways such as regulation, signal transduction, cell maintenance, and differentiation make them possible biomarkers and therapeutic targets. The purpose of this review is to summarize the information published in the last two and a half years about the involvement of microRNAs in papillary thyroid carcinoma (PTC). Another goal is to understand the perspective offered by the new findings. Main microRNA features such as origin, regulation, targeted genes, and metabolic pathways will be presented in this paper. We interrogated the PubMed database using several keywords: “microRNA” + “thyroid” + “papillary” + “carcinoma”. After applying search filters and inclusion criteria, a selection of 137 articles published between January 2018–June 2020 was made. Data regarding microRNA, metabolic pathways, gene/protein, and study utility were selected and included in the table and later discussed regarding the matter at hand. We found that most microRNAs regularly expressed in the normal thyroid gland are downregulated in PTC, indicating an important tumor-suppressor action by those microRNAs. Moreover, we showed that one gene can be targeted by several microRNAs and have nominally described these interactions. We have revealed which microRNAs can target several genes at once.

1. Introduction

Given that in the last two and a half years alone, more than 200 articles have been published on the involvement of microRNAs in the pathology of PTC, microRNAs are a hot topic. Several questions arise from the analysis of these studies, for example, how relevant is the information of these studies to daily medical practice; Will this information ever be beneficial for the patients with an aggressive form of papillary carcinoma? Or we design studies on the treadmill pursuing only scientific interest? During the 1970s, Francis Crick asserted what he believed to be the central dogma of molecular biology. Genetic information traveled from deoxyribonucleic acid (DNA) to ribonucleic acid (RNA) through transcription, then from RNA to proteins via translation, meaning proteins were the functional end products of genes. However, after the whole human genome sequencing, it was understood that genes that encoded proteins accounted for less than 2% of the genome. Given the intricacy of cellular processes, genetic information is most likely passed by additional regulatory elements and not only by coding genes [1]. MicroRNAs (miRNAs) are a class of endogenous non-coding RNA molecules ranging from 18 to 22 nucleotides in length. MicroRNA’s constitute only 3% of the human genome but it is believed that they regulate more than half of the protein-coding genes. Mature microRNA can promote or inhibit messenger ribonucleic acid (mRNA) translation and degradation by targeting with precision complementary sequences in 3′UnTranslated Regions (3′UTR). They act both as post-transcriptional regulators of gene expression and as messengers or intercellular signaling [2]. MicroRNAs are involved in central biological processes, including development, organogenesis, tissue differentiation, cell cycles, and metabolism. Alterations in the expression of microRNA contribute to the pathogenesis of the majority of human malignancies (PTC) [3,4]. The most striking evidence that links microRNAs with thyroid cancer is their large alteration in expression in malignant cells compared to benign cells. MicroRNA expression is dysregulated in human cancer through various mechanisms. The most important are amplification or deletion of microRNA genes, abnormal transcriptional control of microRNAs, and epigenetic changes [5]. PTC is the most common thyroid malignancy [6], and it is defined as a malignant epithelial tumor with evidence of follicular differentiation and a series of specific nuclear features [7]. The incidence of PTC is increasing mainly due to improved diagnostic methods such as ultrasound (US) with targeted fine-needle aspiration biopsy (FNAB) [8]. This increase has been predominantly an increase in diagnosing papillary thyroid microcarcinoma (PTMC). PTMC is defined as measuring 1.0 cm or less in the greatest dimension of the tumor [9]. Cervical lymph nodes, lungs, and bones are the most common metastatic sites, brain, liver, and skin involvement is less common. Distant metastases are usually diagnosed through clinical symptoms or suspicious imaging/laboratory findings (abnormal uptake on the post-ablation whole-body scan (WBS). Another diagnostic method can be a positive finding on an F18-fluorodeoxyglucose (F18-FDG) positron emission tomography/computed tomography (PET/CT) evaluation or cross-sectional study prompted by elevated thyroglobulin levels in patients whose post-ablation WBS is negative [10]. Usually, PTC has an excellent prognosis [11]. Therefore, what are the special situations in daily practice that make us need these new potential biological markers for PTC diagnosis, prognosis, and therapeutic targets? The purpose of this review is to summarize the information published in the last two and a half years about the involvement of microRNAs in PTC. It is also to understand the perspective offered by the new findings.

2. Materials and Methods

A literature analysis was performed in MEDLINE using PubMed for studies published from 2018 to June 2020. The following keywords were used: ”microRNA”+ ”papillary”+ “thyroid” + “carcinoma”, which resulted in 466 articles in English. All related abstracts were reviewed and relevant studies that were published in English were selected. We only included papers that had full text available and described the exact method and results regarding microRNA’s signatures in PTC epigenetic mechanism. A selection of 137 eligible articles was the result of our search (Figure 1).

3. Results

Data on microRNAs, the sample source, the regulatory mode of microRNAs, the target genes/proteins of microRNAs, and their effect on PTC cells from the 137 studies were selected and presented in Table 1 [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148].

3.1. Up- and Downregulated microRNAs in Papillary Thyroid Cancer

Out of 139 microRNAs, 106 are downregulated and 33 are upregulated (Table 1). This means that more than a quarter of the described microRNAs have an oncogenic role (oncomiR’s) and the rest of them have a tumor-suppressive role. The dysregulation of microRNA is an important event during the development of papillary thyroid carcinoma. Overexpression of certain microRNA can result in the tumor suppressor genes repression. Down-regulation of specific microRNA can lead to increased expression of oncogenes. Overexpression and downregulation induce malignant effects on cell cycle progression, proliferation, migration, and apoptosis, leading to tumor growth and progression in PTC and other types of malignancies [1].

3.2. One Gene Can Be Targeted by Several microRNAs

Analyzing, individually, in each study, the interaction between microRNAs and the genes targeted by them, we noticed that the same gene can be targeted by different microRNAs. For example, HMGB1 has been reported to play an important role in promoting both cell survival and death by regulating multiple signaling pathways, including proliferation, autophagy, inflammation, invasion, and metastasis. The study by Ding. C et al. [127] indicates that microRNA-let-7e downregulates HMGB1 expression by directly targeting the HMGB1 3′-UTR, downregulated HMGB1 inhibits PTC cell proliferation and metastasis [127]. MicroRNA-1179 interacted with the 3′ UTR of HMGB1 and suppressed HMGB1 expression at the post-transcriptional level and indicates that the microRNA-1179/MHGB1 pathway plays a tumor suppressor role in PTC [97]. The same gene-HMGB1 is involved in ANRIL/HMGB1/ microRNA-320a pathway. Propofol-mediated ANRIL downregulation competed with HMGB1 to bind microRNA-320a, thus inhibiting PTC cell malignant behaviors [42].
A study by Chen et al. [18] has shown that enforced expression of microRNA-202-3p inhibited WNT signaling by downregulating β-catenin expression in PTC. Again, the same gene is regulated by microRNA-3619-3p to promote cell migration and invasion in PTC [102]. WNT1 has been shown to promote cancer progression because it triggers cell proliferation and metastasis, microRNA-329 inhibits papillary thyroid cancer progression via direct targeting WNT1 [90]. WNT5a, an important signaling molecule in the non-canonical Wnt family, has been involved in nearly all parts of the non-canonical Wnt pathway. The invasion and metastasis of PTC cells were inhibited by microRNA-26a- 5p via Wnt5a [66].
B-cell lymphoma-2 (Bcl-2), an oncogene expressed in most thyroid carcinomas, is also found to be a target of several different microRNAs. MicroRNA-21-5p suppressed Bcl-2 expression [138], silencing LINC00313 led to down-regulation of anti-apoptotic Bcl-2 proteins [136]. Overexpression of miR microARN-203 may serve a role in PTC tumor cells by downregulating Bcl-2 expression [91].
One more targeted gene by multiple microRNAs in PTC is AKT, the human homolog of the viral oncogene v-Akt is related to protein kinases A (PKA) and C (PKC) in humans. The pathway that involves AKT inactivates several proapoptotic factors, AKT also activates transcription factors which promote anti-apoptotic genes. Overexpression of microRNA-15a inhibited the activation of the AKT pathway, which inhibited cell proliferation and promoted the process of apoptosis [39]. Upregulated microRNA-203 suppresses epithelial-mesenchymal transition (EMT), invasion, proliferation, and migration as well as induces apoptosis of PTC cells via downregulated AKT3 [101]. lncRNA n384546 could regulate the expression of AKT3 by sponging microRNA-145-5p [119]. lncRNA HOTTIP modulated Akt1 expression by regulating microRNA-637 in PTC cell lines [103].
Another example is the Sphingosine kinase (SPHK), an enzyme, catalyzing the formation of the prosurvival second messenger sphingosine-1-phosphate (S1P) from the pro-apoptotic lipid sphingosine. High SPHK expression is correlated with a significant decrease in survival rate in patients with several forms of cancer, including PTC. LncRNA LINC00460 promoted PTC progression via modulating SphK2 through sponging microRNA-613 in PTC [26]. lncRNA LINC00520 accelerates the progression of papillary thyroid carcinoma by serving as a competing endogenous RNA of microRNA-577 to increase SphK2 expression [72]. MicroRNA-128 targets SPHK1 to induce apoptosis and reduce cell proliferation, migration in thyroid cancer cell lines, and inhibits tumor growth [14].
PTEN (phosphatase with tensin homology), an upstream negative regulatory molecule of the PI3K/AKT pathway, is the direct target gene of microRNA-106 [116] and microRNA-21 [134]. MicroRNA-625-3p [24] and microRNA-564 [67] directly target the same gene, AEG-1 (astrocyte elevated gene 1), an important regulator of PTC genesis and development. Yes-associated protein 1 (YAP1) was identified as a target gene of microRNA -205 [44] and microRNA-200a-3p [89]. Both microRNA-361-5p [46] and microRNA-26a [92] target ROCK1 (Rho-associated coiled-coil kinase 1), which was closely associated with poor PTC prognosis [46]. Zinc Finger E-Box Binding Homeobox 1 (ZEB1) a gene that plays vital roles in the metastasis of cancer, is inhibited by microRNA-451a [80] and a direct target of microRNA-429 [31].
From the same families of genes discovered to be the target of several microRNAs we mention CXCL-12/16 [16,86], CCNG-1/2 [17,100], IRS-1/2 [19,107], FGF-2/FR [28,112], CCDC-6/67 [52,128], FOX-O1/E1/M1 [27,55,76], ITGA-3/6 [55,61], SL-1A5/25A1 [56,118], MAP-2K4/K1/4K3 [71,78,120], and SOX 11/12/2 [84,95,117].

3.3. One MicroRNA Can Target Several mRNAs/Genes

One microRNA does not target only one but several mRNA/genes, as it was stated before. In our study, we found several microRNAs with multiple genes targeted. For instance, microRNA-146b-5p, downregulated CCDC6 expression by binding to its 3′-UTR in the study by Jia et al. [128] and promoted the expression of MALAT1 by negatively regulating DNMT3A in the study by Peng et al. [63]. The same microRNA-146b, but with the 3p strand located in the reverse position compared to the 5p strand which is present in the forward (5′-3′) position, meaning microRNA-146b-3p, is targeting directly NF2 [132]. From the same family, microRNA-146a targets GABPA [58], and microRNA-146 targets KIT [114]. MicroRNA-199a-5p inhibited cell migration, invasion, and EMT by targeting SNAI in PTC [60] but also attenuated cell proliferation, induced apoptosis, and arrested cells in the G0/G1 phase through regulating the expression of SLC1A5 [118]. From the same family, microRNA-199b-5p suppressed PTC cell aggressiveness by targeting STON2 [65]. MicroRNA-101 suppresses the proliferation, apoptosis resistance, invasion, and migration of PTC cells by directly targeting CXCL12 [16]. MicroRNA-101-3p deficiency enhanced the expression level of FN1, which therefore promoted the RAI (radioactive iodine)-resistance of PTC [49]. Another example is microRNA-150 which serves a key function in suppressing the malignant growth and aggressive behavior of PTC cells through the downregulation of MUC4 [22]. Overexpression of microRNA-150-5p regulated cell proliferation, metastasis, and apoptosis by regulating BRAFV600E [94]. Both the IGF1R [139] and E2F7 [32] genes are targeted directly by the microRNA-30a. MicroRNA-203 inhibits proliferation and motility, and induces apoptosis of PTC cells via regulation of the expression of Bcl-2 [91], and suppresses EMT, invasion, proliferation, and migration of PTC cells via downregulated AKT3 [101]. Five more genes are found to be the target of the same microRNA in four different studies. VHL [104], Bcl-2 [138], PTEN [134], TGFBI [122], and COL4A1 [122] are all targeted genes by microRNA-21. There are still more examples of the same microRNA’s but with the 3p strand located in the reverse position compared to 5p strand which is present in the forward (5′-3′) position, that target different genes: [52,108], [119,129], [29,140], [37,73], [39,131], [45,135], [48,120], [50,68], [66,92], and [57,117].

4. Discussion

Each microRNA can regulate hundreds of messenger RNAs (mRNAs), while various microRNA can control the same mRNA. Additionally, many microRNAs regulate and are regulated by other species of non-coding RNAs, such as circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs). For this reason, it is extremely difficult to predict, study, and analyze the precise role of a single microRNA involved in human cancer, considering the complexity of its connections. Focusing on a single microRNA molecule represents a limited approach. Additional information could come from network analysis, which has become a common tool in the biological field to better understand molecular interactions [1].
Most studies assess the level of expression of the microRNA in question, show the actions of its overexpression/silencing on cell lines, find the gene targeted by the microRNA, and how the metabolic pathway microRNA / target gene works. Although complex information is presented, at the end of the discussion chapter we find the same dry phrase “microRNA-X could be a potential therapeutic/diagnostic/prognostic target for PTC treatment”. Despite this, there are several articles with a different study design that offer something more than “could be”. One of them is the study of Zhao. L et al. [134] which finds Matrine, a traditional Chinese medicine, as an alternative drug for PTC treatment. Treatment with matrine at the concentrations of 1, 2, 5, 10, and 20 mg/ml inhibited TPC 1 cell proliferation by up to 95.8% (for 20 mg/ml matrine). Matrine induced apoptosis and G1 cell cycle arrest through downregulating microRNA-21 to affect the PTEN/Akt signaling in TPC 1 human thyroid cancer cells. Liu. F et al. [121] discovered that microRNA-206 contributed to euthyrox resistance in PTC cells through blockage p38 and JNK signaling pathway by targeting MAP4K3. Another study by Liu et al. [49], found the promoting gene and the signaling pathway regulating RAI-resistance in PTC. The results attested that NEAT1 was upregulated in RAI-resistant PTC accompanied microRNA-101-3p inhibition, FN1 overexpression, and PI3K/AKT signaling pathway abnormal activation. Fang. T et al. [23] discovered that Shenmai injection (SMI), a traditional Chinese formula mainly made up of Red Ginseng and Radix Ophiopogonis. SMI inhibits the differentiation of CD4 + T cells into Treg cells via the microRNA-103/GPER1 axis, which improves the immunological function of PTC patients with postoperative 131-Iodine ablation. Although few, these studies differ in the classical approach to the use of microRNAs in papillary thyroid carcinomas and should be recognized as at least promising.
Even if in the world of publications microRNA is a hot topic, when we talk about PTC, most international guidelines regarding thyroid cancer management, do not even mention microRNA. Here we refer to the NCCN 2018 [149], ETA 2019 [7], and ESMO 2019 [11] guidelines. The exception is the ATA 2015 guideline, which, although published several years before the above-listed guidelines, mentions microRNA as an additional diagnostic molecular marker strategy under development. microRNA markers have shown initial diagnostic utility in FNA samples with indeterminate cytological diagnoses, but they have not been thoroughly validated. It is also mentioned about microRNA, also in this guide, in the chapter “Directions for future research”, as possible progress in identifying markers of thyroid cancer. To result in a significantly improved accuracy of cancer detection in thyroid nodules as compared to the currently available clinical tests [8].
Hence, which are the most challenging parts in PTC management where we could use microRNA? After the clinical and ultrasound evaluation of a thyroid nodule, if malignancy criteria are present, a fine needle biopsy is performed for cytological examination. Some results of the cytological examination can be inconclusive. In such cases, there is a need to assess molecular markers to make a presurgical differentiation of benign and malign lesions. MicroRNAs are one of the novel classes of molecular markers that are being used to improve the diagnosis of thyroid cancer. Several studies have shown that a microRNA-based signature in FNABs can be used to discriminate benign from malignant thyroid nodules. MicroRNA profiling of thyroid cancers can also provide prognostic information useful for defining optimal management strategies. Expression levels of certain microRNA in thyroid tumor tissues are associated with clinicopathological characteristics, such as tumor size, multifocality, capsular invasion, extrathyroidal extension, and both lymph node and distant metastases [150]. Treatment options have been proposed and implemented based on the results obtained from research conducted on epigenetic alterations. Therefore, the development of new therapeutic strategies based on targeting epigenetic changes to restore the expression of tumor suppressor microRNAs or to blunt overexpressed oncogenic microRNAs may provide a new landscape for the treatment of aggressive PTC [151].
Although PTMC generally has an excellent prognosis, the long-term rate of recurrence of PTMC has been reported to be as high as 10% [9]. Currently, there are no reliable clinical features including molecular markers, that can differentiate PTMC in patients who develop progressive disease from indolent PTMC. Even so, searching the PubMed database, regarding microRNA signatures in PTMC, there is only one study by Zhang et al. which combines serum microRNA with ultrasound profile as predictive biomarkers of diagnosis and prognosis for PTMC. In this study, microRNAs were found to be significantly associated with a poor prognosis of patients with PTMC and could be used as prognostic molecular markers or patients with PTMC before and after surgery. These results suggest that circulating microRNAs may be useful as non-invasive molecular biomarkers of diagnosis and prognosis for PTMC [9], selecting those cases that need aggressive therapies, despite the histology of PTMC. Given the need for more studies in this field, this topic could be a research idea for the future, in the era of personalized medicine.

5. Conclusions

Research regarding microRNAs in PTC is undergoing a tremendous shift, suggesting rapid maturation of this field. In this review, we tried to represent as briefly as possible the interactions of microRNAs with target proteins. We also showed microRNAs regulation mode and its effect on PTC cells. Our results showed that a gene can target multiple microRNAs simultaneously, and vice versa. All this information can be used to find the most effective therapeutic targets/biomarkers in PTC. For future research, we indicated a possible niche, namely microRNA signatures in PTMC.

Author Contributions

Conceptualization, L.H., A.P., D.P. Data curation, L.H., A.-C.H., K.G.; Formal analysis, E.-A.B., A.P.; Investigation, L.H., D.P., P.-A.Ș.; Methodology, A.P., A.-C.H., D.P.; Supervision, D.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Study selection summary.
Figure 1. Study selection summary.
Cancers 12 03118 g001
Table 1. Targets of epigenetic alterations in papillary thyroid carcinoma (PTC).
Table 1. Targets of epigenetic alterations in papillary thyroid carcinoma (PTC).
miRNASample SourcesUp/Down-RegulatedTargeted GenemiRNA Effect on PTC CellsSponging/SequesteringPotential UtilityReferences
miR-520a-3ptissueDownJAK1prevented cell proliferation, migration, invasion, promoted apoptosis TTBi. CL et al. [12]
miR-139-5ptissueDownLMO4suppressed cell proliferation, migration, and tumor growthcircBACH2Pr, TTCai. X et al. [13]
miR-128tissueDownSPHK1elevated apoptosis increased G0/G1 arrest, reduced Cyclin D1/ CDK4 expressions-TTCao. XZ et al. [14]
miR-2861tissueUpDGCR5promoted cell proliferation and invasionlncRNA DGCR5PgChen. F et al. [15]
miR-101tissueDownCXCL12repressed cell proliferation, migration, and invasion. Enhanced apoptosis-Pg, TTChen. F et al. [16]
miR-135b-5ptissueUpCCNG2modulated tumor cells proliferation, apoptosis, migrationlncRNA GAS8-AS1TTChen. N et al. [17]
miR-202-3ptissueDownWNTsuppressed the expression of β-catenin, cell migration, and invasion-TTChen. J et al. [18]
miR-1271tissueUpIRS1suppressed migration, invasion, and proliferation of PTC cells-TTChen. Y et al. [19]
miR-153-3ptissueDownZNRF2regulated cell proliferation, migration, and invasionlncRNA TTN-AS1TTCui. Z et al. [20]
miR-548c-3ptissueDownHIF1αreducted N-cadherin and vimentin expression-Pg, TTDu. Y et al. [21]
miR-150tissueDownMUC4suppressed PTC cell proliferation and metastasis-Dg, TTFa. Z et al. [22]
Ex-miR-103bloodUpGPER1influenced the differentiation of CD4 + T cell into Treg cells-TTFang. T et al. [23]
miR-625-3ptissueUpAEG-1promoted the proliferation, migration, and invasion of thyroid cancer cells-TTFang. L et al. [24]
miR-141-3ptissueDownYY-1inhibited cell growth, induced apoptosis, and suppressed invasion-Pg, TTFang. M et al. [25]
miR-613tissueDownSphK2inhibited cell proliferation, migration, and invasionlncRNA LINC00460TTFeng. L et al. [26]
miR-93-3p-660tissueUpFOXO1inhibited glycolysis that attenuated glucose uptake and lactate productionlncRNA ASMTL-AS1TTFeng. Z et al. [27]
miR-1266tissueDownFGFR2inhibited PTC cell proliferation, migration, and invasion-Dg, TTFu. YT et al. [28]
miR-129tissueUpMAL2suppressed growth and invasion of PTC cells-Pv, TTGao. X et al. [29]
miR-791tissueDown-inhibited proliferation of PTC cells via blocking the G1 phase-Pg, TT Gao. XB et al. [30]
miR-429tissueDownZEB1inhibited cell proliferation, migration, and invasionlncRNA SNHG22Dg, TTGao. H et al. [31]
miR-30atissueDownE2F7inhibited the proliferation, migration, and invasion of PTC cells-TTGuo. H et al. [32]
miR-9-5ptissueDownBRAFsuppressed the viability of PTC cells by inducing apoptosis-TTGuo. F et al. [33]
miR-215tissueDownARFGEF1inhibited proliferation and metastasis-PgHan. J et al. [34]
Ex-miR-199bloodDownDLG1-AS1suppressed proliferation of PTC cells-DgHe. T et al. [35]
miR-1252tissueUpFSTL1inhibited viability, proliferation, and stimulated apoptosis in PTC cells.hsa_circ_ 0011290TTHu. Z et al. [36]
miR-486-5ptissueDownKIAA1199inhibited cell growth of PTC-TTJiao. X et al. [37]
miR-885-5ptissueDownRAC1suppressed PTC cell proliferationhsa_circ_ 0004458TTJin. X et al. [38]
miR-15atissueDownRET/AKTinhibited PTC cell proliferation and invasion and enhanced the apoptosis-TTJin. J et al. [39]
miR-381-3ptissueDownLRP6inhibited the proliferation and metastasis of PTC cells-TTKong. W et al. [40]
miR-485-5ptissueDownRaf1inhibited PTC cell proliferation, migration and invasionLncRNA LINC00460TTLi. G et al. [41]
miR-320acell cultureUpHMGB1inhibited cell proliferation, migration and invasion rateslncRNA ANRILPv, TTLi. M et al. [42]
miR-369-3pcell cultureDownTSPAN13suppressed cell proliferation, colony formation, and induced apoptosis in PTC-Dg, Pv, TTLi. P et al. [43]
miR-205tissueDownYAP1inhibited proliferation and invasion of thyroid cancer cells-TTLi. D et al. [44]
miR-204-3ptissueDownCDC23suppressed PTC proliferation, migration and invasionlncRNA LINC00514TTLi. X et al. [45]
miR-361-5ptissueDownROCK1Inhibited proliferation, migration, and invasion-TTLi. R et al. [46]
miR-4500cell cultureDownPLXNC1inhibited cell viability, colony formation, and cell apoptosis-Pg, TTLi. R et al. [47]
miR-211-5ptissueDownSPARCsuppressed proliferation, migration, and invasion of thyroid tumor cellslncRNA MCM3AP-AS1TTLiang. M et al. [48]
miR-101tissueDownFN1promoted the RAI-resistance in PTClncRNA-NEAT1TTLiu. C et al. [49]
miR-214tissueDownPSMD10suppressed proliferation, and induced cell apoptosis and cell cycle arrest in PTC cells-TTLiu. F et al. [50]
miR-744tissueDownNOB1attenuated the proliferation and invasion of PTC cells-TTLiu. H et al. [51]
miR-96-5ptissueUpCCDC67accelerated the proliferation and metastasis of PTC cells-Dg, TTLiu. ZM et al. [52]
miR-4728cell cultureDownSOS1repressed the PTC cell proliferation through MAPK-Dg, TTLiu. Z et al. [53]
miR-431tissueDownGli1inhibited cell migration and invasion of PTC-TTLiu. Y et al. [54]
miR-524-5ptissueDownFOXE1, ITGA3suppressed PTC progression by regulating tumor cell proliferation, migration, and invasion-TTLiu. H et al. [55]
miR-331-3ptissueDownSLC25A1inhibited PTC cells proliferation, migration and invasionlncRNA-BRMTTLiu. S et al. [56]
miR-335-5ptissueDownICAM1reduced the proliferation, migration, invasion of PTC-TTLuo. L et al. [57]
miR-146atissue-GABPAsuppressed proliferation, migration, and invading capabilities of PTC cells TTLong. M et al. [58]
miR-29a-3ptissueDownOTUB2suppressed growth, proliferation, invasion in PTC cells.-Pg, TTMa. Y et al. [59]
miR-199a-5ptissueDownSNAI1reduced migration and invasion of PTC cells-TTMa. S et al. [60]
miR-363-3ptissueDownITGA6suppressed anoikis resistance in PTC cells-TTPan. Y et al. [61]
miR-1231, miR-1304tissueDown-inhibited proliferation and invasion of PTC cellscirc_ 0025033TTPan. Y et al. [62]
miR-146b-5ptissueUpDNMT3Aaccelerated extra-glandular invasion and metastasis of PTC cellslncRNA-MALAT1Dg, TTPeng. Y et al. [63]
miR-448tissueDownKDM5Binhibited PTC cell progression and tumor growth via TGIF1-TTPu. Y et al. [64]
miR-199b-5ptissueDownSTON2inhibited PTC cell growth and metastasis-TTRen. L et al. [65]
miR-26a-5ptissueDownWnt5ainhibited proliferation, colony formation, invasion, and migration of PTC cells.-TTShi. D et al. [66]
miR-564tissueDownAEG-1inhibited cell proliferation, migration, and invasion and induced cell apoptosis-TTSong. Z et al. [67]
miR-214-3ptissueDownPSMD10impaired PTC cell proliferation and metastasislncRNA-SNHG3TTSui. G et al. [68]
miR-144tissueDownWWTR1inhibited of PTC cell proliferation-Pg, TTSun. W et al. [69]
miR-106b-5ptissueDownATAD2induced apoptosis and suppressed invasion of PTC cellslncRNA-NEAT1_2TTSun. W et al. [70]
miR-124-3pcell cultureDownMAP2K4inhibited the proliferation, induced apoptosis and cell cycle arrest in PTC cells-TTSun. Y et al. [71]
miR-577tissueDownSphk2inhibited PTC cell proliferation, migration, and invasionlncRNA-LINC00520Dg, TTSun. Y et al. [72]
miR-486tissueDownTENM1inhibited proliferation, invasion, and migration of PTC cell-TTSun. YH et al. [73]
miR-497tissueDownBDNFsuppressed PTC cell proliferation, migration, and invasionlncRNA-LINC00152TTSun. Z et al. [74]
miR-22tissueUp-promoted PTC cell metastasis and BRAFV600E mutation-Dg, PgWang. D et al. [75]
miR-599tissueDownHey2diminished PTC cell proliferation, migration, invasion, while stimulating apoptosis-Pr, TTWang. DP et al. [76]
miR-3619-5pcell cultureDownFOXM1regulated proliferation and apoptosis in PTClncRNA-Linc01410TTWang. G et al. [77]
miR-675tissueDownMAPK1suppressed PTC cell proliferation, migration, and invasionlncRNA-RMRPTTWang. J et al. [78]
miR-1258cell cultureDownTMPRSS4inhibited cell viability, migration, and invasion-Dg, TTWang. L et al. [79]
miR-451atissueDownZEB1suppressed proliferation, mobility, and invasion of PTC cell-TTWang. Q et al. [80]
miR-622tissueDownVEGFAinhibited PTC cell proliferation, migration, and invasion-TTWang. R et al. [81]
miR-212tissueDownMIATinhibited PTC cell proliferation, migration, and invasion.(possible) lncRNA-MIATTTWang. R et al. [82]
miR-718tissueDownPDPK1inhibited PTC cell growth, reduced cell invasion, repressed glucose metabolism-Dg, TTWang. X et al. [83]
miR-31tissueDownSOX11repressed PTC cell proliferation, invasion, and migration-TTWang. Y et al. [84]
miR-384tissueDownPRKACBsuppressed PTC cell proliferation and migration-TTWang. Y et al. [85]
miR-873tissueDownCXCL16inhibited proliferation, migration, and invasion of the PTC cells-TTWang. Z et al. [86]
miR-143-3ptissueDownMSI2induced apoptosis, suppresses invasion and migration of PTC -TTWang. ZL et al. [87]
miR-1261tissueDownC8orf4inhibited PTC cell proliferation, migration, and invasioncircZFRTTWei. H et al. [88]
miR-200a-3ptissueDownYAP1inhibited PTC cell proliferation and promoted apoptosislncRNA-SNHG15TTWu. DM et al.
[89]
miR-329tissueDownWNT1decreased PTC cell proliferation, colony formation, suppressed growth-TTWu. L et al. [90]
miR-203tissueDownBcl-2inhibited cell proliferation, induced apoptosis, and suppressed the motility of PTC cells-TTWu. X et al. [91]
miR-26atissueDownROCK1repressed PTC cell viability, invasion, and metastasis-Dg, TTWu. YC et al. [92]
miR-222tissueUp-correlated with capsular invasion, vascular invasion, tumor size and metastasis-PgXiang. D et al. [93]
miR-150-5pcell cultureUpBRAF(V600E)promoted PTC cell proliferation, suppressed apoptosis-TTYan. R et al. [94]
miR-423-5pcell cultureDownSOX12suppressed PTC cell proliferation and invasionlncRNA-NR2F1-AS1TTYang. C et al. [95]
miR-182tissueUpCHL1 *correlated with extrathyroidal invasion, cervical lymph node metastasis, and TNM -PgYao. XG et al. [96]
miR-1179tissue-HMGB1-circFOXM1TTYe. M et al. [97]
miR-1270cell cultureUpSCAIpromoted PTC cell proliferation, migration-TTYi. T et al. [98]
miR-761tissueDownTRIM29inhibited cell proliferation, and cell cycle progression in PTClncRNA- HOXA11-ASTTYin. X et al. [99]
miR-23a-tissueDownCCNG1decreased proliferation, induced cell cycle arrest, and promoted PTC cell apoptosis-Dg, TTYin. JJ et al. [100]
miR-203tissueDownAKT3suppressed cell migration and invasion in the PTC cells and promoted cell apoptosis-TTYou. A et al. [101]
miR-3619-3ptissueUpWntpromoted PTC cell migration and invasion-TTYu. S et al. [102]
miR-637tissueDownAkt1inhibit inhibited PTC cell proliferation, invasion, and migrationlncRNA HOTTIPDg, TTYuan. Q et al. [103]
miR-21tissueUpVHLpromoted PTC cell proliferation and invasion-TTZang. C et al. [104]
miR-224-5ptissueUpEGR2promoted PTC cell
migration, invasion
-Dg, TTZang. CS et al. [105]
miR-509tissueDownPAX9inhibited cell proliferation and invasion in papillary thyroid carcinoma-TTZhang. S et al. [106]
miR-766tissueDownIRS2inhibited proliferation of PTC cells-TTZhao. J et al. [107]
miR-96-3ptissueUpSDHBincreased the invasion and migration of PTC cells TTZhao. X et al. [108]
miR-138-5ptissueDownLRRK2inhibited PTC cell proliferation, apoptosislncRNA RP11-476D10.1TTZhao. Y et al. [109]
miR-409-3ptissueDownCCND2negatively regulated PTC cell proliferation and cell cycle progression-Pr, TTZhao. Z et al. [110]
miR-200b/ctissueDownRap1binhibited PTC cell invasion, migration and growth-TTZhou. B et al. [111]
miR-188-5ptissueDownFGF-5 *suppressed PTC cells growth-TTZhou. P et al. [112]
miR-506tissueDownIL17RDinhibited the proliferation, invasion, and migration capacities of PTC cells-Pg, TTZhu. J et al. [113]
miR-146tissueUp *KITpromoted PTC cell proliferation and invasion *lncRNA CTCTTLiao. B et al. [114]
miR-1178tissueUpTLR4promoted cell proliferation and suppressed cell apoptosiscirc_FNDC3BTTWu. G et al. [115]
miR-106atissueUpPTEN/
SFR4
enhanced PTC cell proliferative, migratory and invasive abilitieslncRNA-HULCTTYang. Z et al. [116]
miR-335tissueDownSOX2suppressed the proliferation, migration, and invasion of PTC cellslncRNA-LINC01510TTLi. Q et al. [117]
miR-199a-5ptissueDownSLC1A5attenuated proliferation, induced apoptosis, and arrested cells in the G0/G1 phaseABHD11-AS1Dg, TTZhuang. X et al. [118]
miR-145-5ptissueDownAKT3inhibited proliferation, migration and invasionlncRNA-n384546Dg, TTFeng. J et al. [119]
miR-211tissueUpRECKpromoted tumor growth and increased tumor volume in PTC cells-Dg, PgWei. ZL et al. [120]
miR-206tissueDownMAP4K3enhanced Euthyrox sensitivity in Euthyrox-resistant PTC cells-TTLiu. F et al. [121]
miR-21-5pcell cultureUpTGFBI, COL4A1secreted by hypoxic PTC cells is a potent pro-angiogenic factor-Dg, TTWu. F et al. [122]
Ex-miR-423-5pbloodUp-promoted PTC cell migration and invasion-Dg, TTYe. W et al. [123]
miR-422atissueDownSP1suppressed PTC cells proliferation and metastasislncRNA-LINC00313TTYan. D et al. [124]
miR-1301-3ptissueDownSTAT3inhibited PTC cell proliferation, cell apoptosis -acceleratedlncRNA-ABDH11-AS1TTWen. J et al. [125]
miR-let-7atissueDownc-Mycsuppressed PTC cell proliferation, migration, and invasion-TTHuang. J et al. [126]
miR-let-7etissueDownHMGB1inhibited of PTC cell growth and metastasis-TTDing. C et al. [127]
miR-146b-5ptissueUpCCDC6promoted proliferation, migration, invasion, and cell cycle progression of PTC cells-Dg, TTJia. M et al. [128]
miR-145tissueDownZEB2inhibited the migration, invasion, and tumorigenesis of PTC cellscirc_NUP214TTLi. X et al. [129]
miR-520c-3ptissueDownS100A4inhibited PTC cells proliferationlncRNA-HOXA-AS2TTXia. F et al. [130]
miR-15a-5ptissueDown-inhibited PTC cells growthlncRNA-HOXA-AS2TTJiang. L et al. [131]
miR-146b-3ptissueUpNF2increased PTC cell migration and invasion-TTYu. C et al. [132]
miR-22a-3ptissueUpCBLpromoted PTC cell proliferation and invasioncirc_ITCHTTWang. M et al. [133]
miR-21cell culture-PTENmatrine- induced apoptosis and G1 cell cycle arrest -TTZhao. L et al. [134]
miR-204tissueDownBRD4inhibited of PTC cell proliferationlncRNA-UCA1TTLi. D et al. [135]
miR-4429tissueDownBcl-2suppressed PTC cell proliferation, promoted apoptosis, and induced cell cycle arrest in G2/M phaselncRNA-LINC00313TTWu. JW et al. [136]
miR-222tissueUp *PPP2R2Apromoted PTC cell migration and invasion-Dg, TTHuang. Y et al. [137]
miR-21-5ptissueDownBcl-2inhibited TPC cell
proliferation and invasion
lncRNA-BISPRDg, TTZhang. H et al. [138]
miR-30atissueDownIGF1Rinhibited PTC cell proliferation, cycle progression, invasion, migrationlncRNA-PVT1TTFeng. K et al. [139]
miR-129-5ptissueDownKLK7inhibited proliferation, cell survival, invasion, and migrationlncRNA-NEAT1TTZhang. H et al. [140]
Ex-miR-146b-5p, Ex-miR-222-5pbloodDown-enhanced the migration and invasion activity of PTC cells-PgJiang. K et al. [141]
miR-539tissueDownSLPIinhibited PTC cell EMT and tumor growth -TTXu. CB et al. [142]
miR-24-3ptissueUpp27kip1regulated PTC cell proliferation, apoptosis migration and invasionncRNA-MIR22HGTTChen. ZB et al. [143]
miR-26acell cultureDownARPP19promoted proliferation of PTC cells-TTGong. Y et al. [144]
Ex-miR-98-5pbloodDownHMGA2promoted PTC cell growth, inhibited apoptosis-Dg, PgQiu. K et al. [145]
miR-296-5ptissueDownPLK1suppressed cell proliferation, inhibited cell clone formation, arrested the cell cycle in G2/M phase, and induced apoptosis-TTZhou. SL et al. [146]
miR-451acell cultureDown *PSMB8inhibited proliferation, EMT and induced apoptosis of PTC cells-TTFan. X et al. [147]
miR-630tissueDownJAK2/
STAT3
suppressed migration and invasion of PTC cells-TTPan. XM et al. [148]
TT—therapeutic target, Dg-Diagnosis, Pg—Prognostic, Pr—Prevention, * The feature discovered in another study than the one cited.
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Hitu, L.; Gabora, K.; Bonci, E.-A.; Piciu, A.; Hitu, A.-C.; Ștefan, P.-A.; Piciu, D. MicroRNA in Papillary Thyroid Carcinoma: A Systematic Review from 2018 to June 2020. Cancers 2020, 12, 3118. https://doi.org/10.3390/cancers12113118

AMA Style

Hitu L, Gabora K, Bonci E-A, Piciu A, Hitu A-C, Ștefan P-A, Piciu D. MicroRNA in Papillary Thyroid Carcinoma: A Systematic Review from 2018 to June 2020. Cancers. 2020; 12(11):3118. https://doi.org/10.3390/cancers12113118

Chicago/Turabian Style

Hitu, Liviu, Katalin Gabora, Eduard-Alexandru Bonci, Andra Piciu, Adriana-Cezara Hitu, Paul-Andrei Ștefan, and Doina Piciu. 2020. "MicroRNA in Papillary Thyroid Carcinoma: A Systematic Review from 2018 to June 2020" Cancers 12, no. 11: 3118. https://doi.org/10.3390/cancers12113118

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