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Noncoding RNAs in Cancer: From Cancer Stem Cells to Invasion and Metastases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 19834

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Dr. Paola Parrella

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Guest Editor

IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
Interests: breast cancer; lung cancer; gliomas; colon cancer; miRNA; biomarkers

Special Issue Information

Dear Colleagues,

Over the past decade, the widespread implementation of microarrays and next-generation sequencing technologies to whole genomes and transcriptomes analyses has brought into light that while about 1.5% of the genome encodes proteins, at least 75% is actively transcribed into noncoding RNAs (ncRNAs). This includes short RNA molecules such as microRNAs (22-25 bp) and transcripts longer than 200 bp named long noncoding RNAs (lncRNAs). LncRNAs represent the largest family of noncoding transcripts, including long intergenic ncRNAs (lincRNAs), enhancer ncRNAs (eRNAs), natural antisense transcripts (NATs), circular RNAs (circRNAs), and transcribed ultraconserved regions (T-UCRs). The functional relevance of ncRNAs for cancer transformation and progression has been widely documented, as their aberrant expression may affect virtually any oncogenic cascade underlying the typical cancer hallmarks. Cancer stem cells possess the ability to self-renew and differentiate into nontumorigenic progeny, driving tumorigenesis and metastatic dissemination. Accumulating evidence indicates that ncRNAs play an important role in cancer stem cell biology and cancer progression, acting as both suppressors or promoters during growth and metastasis. The high cell type-, tissue-, and disease-specificity of ncRNAs has shown, compared to protein coding mRNAs, to make ncRNAs particularly attractive as clinical biomarkers and putative therapeutic targets.

The present Special Issue is aimed at collecting latest advances and outstanding studies investigating the role of noncoding RNAs in the development and progression of cancer and exploring their possible implementation as biomarkers and putative therapeutic targets. Original research and review manuscripts are warmly welcome.

Dr. Paola Parrella
Guest Editor

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Keywords

Noncoding RNA
Solid tumor
Cancer stem cells
Invasion
Metastases
Epigenetic
Drug response
Gene expression regulation

Published Papers (6 papers)

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Research

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16 pages, 13200 KiB

Open AccessArticle

PLEKHA8P1 Promotes Tumor Progression and Indicates Poor Prognosis of Liver Cancer

by Jiyeon Lee, Ji-Hyun Hwang, Harim Chun, Wonjin Woo, Sekyung Oh, Jungmin Choi and Lark Kyun Kim

Int. J. Mol. Sci. 2021, 22(14), 7614; https://doi.org/10.3390/ijms22147614 - 16 Jul 2021

Cited by 8 | Viewed by 3496

Abstract

Hepatocellular carcinoma (HCC) records the second-lowest 5-year survival rate despite the avalanche of research into diagnosis and therapy. One of the major obstacles in treatment is chemoresistance to drugs such as 5-fluorouracil (5-FU), making identification and elucidation of chemoresistance regulators highly valuable. As the regulatory landscape grows to encompass non-coding genes such as long non-coding RNAs (lncRNAs), a relatively new class of lncRNA has emerged in the form of pseudogene-derived lncRNAs. Through bioinformatics analyses of the TCGA LIHC dataset, we have systematically identified pseudogenes of prognostic value. Initial experimental validation of selected pseudogene-derived lncRNA (PLEKHA8P1) and its parental gene (PLEKHA8), a well-studied transport protein in Golgi complex recently implicated as an oncogene in both colorectal and liver cancer, indicates that the pseudogene/parental gene pair promotes tumor progression and that their dysregulated expression levels affect 5-FU-induced chemoresistance in human HCC cell line FT3-7. Our study has thus confirmed cancer-related functions of PLEKHA8, and laid the groundwork for identification and validation of oncogenic pseudogene-derived lncRNA that shows potential as a novel therapeutic target in circumventing chemoresistance induced by 5-FU. Full article

(This article belongs to the Special Issue Noncoding RNAs in Cancer: From Cancer Stem Cells to Invasion and Metastases)

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13 pages, 1944 KiB

Open AccessArticle

Human Endometrial Carcinogenesis Is Associated with Significant Reduction in Long Non-Coding RNA, TERRA

by Meera Adishesh, Rafah Alnafakh, Duncan M. Baird, Rhiannon E. Jones, Shannon Simon, Lucy Button, Areege M. Kamal, John Kirwan, S. Bridget DeCruze, Josephine Drury, Gabriele Saretzki and Dharani K. Hapangama

Int. J. Mol. Sci. 2020, 21(22), 8686; https://doi.org/10.3390/ijms21228686 - 18 Nov 2020

Cited by 8 | Viewed by 2239

Abstract

Telomeres are transcribed as long non-coding RNAs called TERRAs (Telomeric repeat containing RNA) that participate in a variety of cellular regulatory functions. High telomerase activity (TA) is associated with endometrial cancer (EC). This study aimed to examine the levels of three TERRAs, transcribed at chromosomes 1q-2q-4q-10q-13q-22q, 16p and 20q in healthy (n = 23) and pathological (n = 24) human endometrium and to examine their association with cellular proliferation, TA and telomere lengths. EC samples demonstrated significantly reduced levels of TERRAs for Chromosome 16p (Ch-16p) (p < 0.002) and Chromosome 20q (Ch-20q) (p = 0.0006), when compared with the postmenopausal samples. No significant correlation was found between TERRA levels and TA but both Ch-16p and Ch-20q TERRA levels negatively correlated with the proliferative marker Ki67 (r = −0.35, p = 0.03 and r = −0.42, p = 0.01 respectively). Evaluation of single telomere length analysis (STELA) at XpYp telomeres demonstrated a significant shortening in EC samples when compared with healthy tissues (p = 0.002). We detected TERRAs in healthy human endometrium and observed altered individual TERRA-specific levels in malignant endometrium. The negative correlation of TERRAs with cellular proliferation along with their significant reduction in EC may suggest a role for TERRAs in carcinogenesis and thus future research should explore TERRAs as potential therapeutic targets in EC. Full article

(This article belongs to the Special Issue Noncoding RNAs in Cancer: From Cancer Stem Cells to Invasion and Metastases)

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13 pages, 1530 KiB

Open AccessArticle

Sinomenine Inhibits Migration and Invasion of Human Lung Cancer Cell through Downregulating Expression of miR-21 and MMPs

by Kun-Hung Shen, Jui-Hsiang Hung, Yi-Ching Liao, Shu-Ting Tsai, Ming-Jiuan Wu and Pin-Shern Chen

Int. J. Mol. Sci. 2020, 21(9), 3080; https://doi.org/10.3390/ijms21093080 - 27 Apr 2020

Cited by 39 | Viewed by 3065

Abstract

Sinomenine is an alkaloid derived from Sinomenium acutum. Recent studies have found that sinomenine can inhibit various cancers by inhibiting the proliferation, migration and invasion of tumors and inducing apoptosis. This study aims to investigate the effect and mechanism of sinomenine on inhibiting the migration and invasion of human lung adenocarcinoma cells in vitro. The results demonstrate that viabilities of A549 and H1299 cells were inhibited by sinomenine in a dose-dependent manner. When treated with sub-toxic doses of sinomenine, cell migration and invasion are markedly suppressed. Sinomenine decreases the mRNA level of matrix metalloproteinase-2 (MMP-2), MMP-9, and the extracellular inducer of matrix metalloproteinase (EMMPRIN/CD147), but elevates the expression of reversion-inducing cysteine-rich proteins with kazal motifs (RECK) and the tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2. In addition, sinomenine significantly increases the expression of the epithelial marker E-cadherin but concomitantly decreases the expression of the mesenchymal marker vimentin, suggesting that it suppresses epithelial–mesenchymal transition (EMT). Moreover, sinomenine downregulates oncogenic microRNA-21 (miR-21), which has been known to target RECK. The downregulation of miR-21 decreases cell invasion, while the upregulation of miR-21 increases cell invasion. Furthermore, the downregulation of miR-21 stimulates the expression of RECK, TIMP-1/-2, and E-cadherin, but reduces the expression of MMP-2/-9, EMMPRIN/CD147, and vimentin. Taken together, the results reveal that the inhibition of A549 cell invasion by sinomenine may, at least in part, be through the downregulating expression of MMPs and miR-21. These findings demonstrate an attractive therapeutic potential for sinomenine in lung cancer anti-metastatic therapy. Full article

(This article belongs to the Special Issue Noncoding RNAs in Cancer: From Cancer Stem Cells to Invasion and Metastases)

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17 pages, 2263 KiB

Open AccessArticle

ABC Efflux Transporters and the Circuitry of miRNAs: Kinetics of Expression in Cancer Drug Resistance

by Bruno C. Gomes, Mónica Honrado, Ana Armada, Miguel Viveiros, José Rueff and António S. Rodrigues

Int. J. Mol. Sci. 2020, 21(8), 2985; https://doi.org/10.3390/ijms21082985 - 23 Apr 2020

Cited by 13 | Viewed by 3136

Abstract

Cancer drug resistance (CDR) is a major problem in therapeutic failure. Over 90% of patients with metastatic cancer present CDR. Several mechanisms underlie CDR, including the increased expression of efflux ABC transporters and epigenetic phenomena. Nevertheless, a topic that is not usually addressed is the mechanism underlying the loss of CDR once the challenge to these cells is withdrawn. A KCR cell line (doxorubicin-resistant, expressing ABCB1) was used to induce loss of resistance by withdrawing doxorubicin in culture medium. ABCB1 activity was analysed by fluorescence microscopy and flow cytometry through substrate (DiOC2) retention assays. The expression of 1008 microRNAs was assessed before and after doxorubicin withdrawal. After 16 weeks of doxorubicin withdrawal, a decrease of ABCB1 activity and expression occurred. Moreover, we determined a signature of 23 microRNAs, 13 underexpressed and 10 overexpressed, as a tool to assess loss of resistance. Through pathway enrichment analysis, “Pathways in cancer”, “Proteoglycans in cancer” and “ECM-receptor interaction” were identified as relevant in the loss of CDR. Taken together, the data reinforce the assumption that ABCB1 plays a major role in the kinetics of CDR, and their levels of expression are in the dependence of the circuitry of cell miRNAs. Full article

(This article belongs to the Special Issue Noncoding RNAs in Cancer: From Cancer Stem Cells to Invasion and Metastases)

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26 pages, 38510 KiB

Open AccessArticle

MicroRNA Assisted Gene Regulation in Colorectal Cancer

by Adewale O. Fadaka, Ashley Pretorius and Ashwil Klein

Int. J. Mol. Sci. 2019, 20(19), 4899; https://doi.org/10.3390/ijms20194899 - 3 Oct 2019

Cited by 17 | Viewed by 3922

Abstract

Colorectal cancer (CRC) is the second-leading cause of cancer death and a major public health problem. Nearly 80% CRC cases are diagnosed after the disease have metastasized and are often too advanced for treatment. Small non-coding RNA guides argonaute protein to their specific target for regulation as the sole of RNA induced silencing complex for gene silencing. These non-coding RNA for example microRNA, are thought to play a key role in affecting the efficiency of gene regulation in cancer, especially CRC. Understanding the mechanism at the molecular level could lead to improved diagnosis, treatment, and management decisions for CRC. The study aimed to predict the molecular mechanism of gene regulation based microRNA-mRNA duplex as a lead in the silencing mechanism. Five candidate microRNAs were identified through the in silico approach. The MicroRNA target prediction and subsequent correlation, and prioritization were performed using miRTarBase, gbCRC and CoReCG, and DAVID databases respectively. Protein selection and preparation were carried out using PDB and Schrödinger suits. The molecular docking analysis was performed using PATCHDOCK webserver and visualized by discovery studio visualizer. The results of the study reveal that the candidate microRNAs have strong binding affinity towards their targets suggesting a crucial factor in the silencing mechanism. Furthermore, the molecular docking of the receptor to both the microRNA and microRNA-mRNA duplex were analyzed computationally to understand their interaction at the molecular level. Conclusively, the study provides an explanation for understanding the microRNAs-based gene regulation (silencing mechanism) in CRC. Full article

(This article belongs to the Special Issue Noncoding RNAs in Cancer: From Cancer Stem Cells to Invasion and Metastases)

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Review

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15 pages, 783 KiB

Open AccessReview

LncRNA MORT (ZNF667-AS1) in Cancer—Is There a Possible Role in Gynecological Malignancies?

by Riccardo Di Fiore, Sherif Suleiman, Rosa Drago-Ferrante, Ana Felix, Sharon A. O’Toole, John J. O’Leary, Mark P. Ward, James Beirne, Angel Yordanov, Mariela Vasileva-Slaveva, Yashwanth Subbannayya, Francesca Pentimalli, Antonio Giordano and Jean Calleja-Agius

Int. J. Mol. Sci. 2021, 22(15), 7829; https://doi.org/10.3390/ijms22157829 - 22 Jul 2021

Cited by 11 | Viewed by 3179

Abstract

Gynecological cancers (GCs) are currently among the major threats to female health. Moreover, there are different histologic subtypes of these cancers, which are defined as ‘rare’ due to an annual incidence of <6 per 100,000 women. The majority of these tend to be associated with a poor prognosis. Long non-coding RNAs (lncRNAs) play a critical role in the normal development of organisms as well as in tumorigenesis. LncRNAs can be classified into tumor suppressor genes or oncogenes, depending on their function within the cellular context and the signaling pathways in which they are involved. These regulatory RNAs are potential therapeutic targets for cancer due to their tissue and tumor specificity. However, there still needs to be a deeper understanding of the mechanisms by which lncRNAs are involved in the regulation of numerous biological functions in humans, both in normal health and disease. The lncRNA Mortal Obligate RNA Transcript (MORT; alias ZNF667-AS1) has been identified as a tumor-related lncRNA. ZNF667-AS1 gene, located in the human chromosome region 19q13.43, has been shown to be silenced by DNA hypermethylation in several cancers. In this review, we report on the biological functions of ZNF667-AS1 from recent studies and describe the regulatory functions of ZNF667-AS1 in human disease, including cancer. Furthermore, we discuss the emerging insights into the potential role of ZNF667-AS1 as a biomarker and novel therapeutic target in cancer, including GCs (ovarian, cervical, and endometrial cancers). Full article

(This article belongs to the Special Issue Noncoding RNAs in Cancer: From Cancer Stem Cells to Invasion and Metastases)

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