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MicroRNA as Biomarkers in Cancer Diagnostics and Therapeutics (II)

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 17715

Special Issue Editor


E-Mail Website1 Website2
Guest Editor
1. Department of Radiology, Michigan State University, Interdisciplinary Science and Technology Building, East Lansing, MI 48824, USA
2. Precision Health Program, Michigan State University, Interdisciplinary Science and Technology Building, East Lansing, MI 48824, USA
Interests: tissue slide-based microRNA diagnostics; microRNA biology and evolution; cell type-specific activities of microRNAs in oncology with a focus on breast and pancreatic cancer; nanoparticle-based delivery of microRNA activity modulators
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

MicroRNAs (miRNAs) are small non-coding RNA molecules that function predominantly as post-transcriptional regulators of gene expression. miRNAs play important roles in development, cellular differentiation and homeostasis, and host–virus interactions. miRNA expression and function are dysregulated in cancer. Specific miRNAs have been shown to exert tumor-promoting or tumor-suppressive functions depending of the expressing cell type and cancer site. Within cancer cells, miRNA can modulate growth and chemoresistance, stem cell, epithelial-to-mesenchymal transition and/or metastatic programs. Within other cell types of the tumor microenvironment, miRNAs can promote angiogenic and immune suppressive programs.

Most miRNAs act in a cell-autonomous fashion within the expressing cell, yet miRNAs are an important cargo in extracellular vesicles that can affect specific biological programs or pathways in recipient cells. There are several examples of miRNA-mediated cell-to-cell communication that impart a favorable microenvironment for cancer cell growth and metastasis. Circulating miRNAs either in extracellular vesicles, multi-protein complexes, or in other forms are readily found and often altered in the blood and other bio-fluids of cancer patients.

This Special Issue will provide a comprehensive update on the latest findings on cancer-associated miRNAs, with a focus on the clinical application of miRNAs as biomarkers for cancer diagnosis and prognosis, and treatment prediction, as well as miRNA-based therapeutic strategies.

Original papers and review articles that describe advances in detection methodology, bioinformatics approaches, and statistical analysis with an impact on the clinical application of miRNAs as cancer biomarkers are welcome.

 

Dr. Lorenzo F. Sempere
Guest Editor

Manuscript Submission Information

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Keywords

  • MicroRNA (miRNA, miR)
  • Tissue analysis
  • Circulating biomarkers (blood, bio-fluids)
  • Extracellular vesicle, exosomes
  • Cancer diagnosis
  • Treatment prediction
  • Therapeutics

Published Papers (6 papers)

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Research

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16 pages, 2189 KiB  
Article
A Bioinformatic Pipeline Places STAT5A as a miR-650 Target in Poorly Differentiated Aggressive Breast Cancer
by Eric López-Huerta and Ezequiel M. Fuentes-Pananá
Int. J. Mol. Sci. 2020, 21(20), 7720; https://doi.org/10.3390/ijms21207720 - 19 Oct 2020
Cited by 1 | Viewed by 2082
Abstract
Breast cancer (BRCA) is a leading cause of mortality among women. Tumors often acquire aggressive features through genomic aberrations affecting cellular programs, e.g., the epithelial to mesenchymal transition (EMT). EMT facilitates metastasis leading to poor prognosis. We previously observed a correlation between an [...] Read more.
Breast cancer (BRCA) is a leading cause of mortality among women. Tumors often acquire aggressive features through genomic aberrations affecting cellular programs, e.g., the epithelial to mesenchymal transition (EMT). EMT facilitates metastasis leading to poor prognosis. We previously observed a correlation between an amplification of miR-650 (Amp-650) and EMT features in BRCA samples isolated from Mexican patients. In this study, we explored the cBioportal database aiming to extend that observation and better understand the importance of Amp-650 for BRCA aggressiveness. We found that Amp-650 is more frequent in aggressive molecular subtypes of BRCA, as well as in high grade poorly differentiated tumors, which we confirmed in an external miRNA expression database. We performed differential expression analysis on samples harboring Amp-650, taking advantage of gene target prediction tools and tumor suppressor gene databases to mine several hundreds of differentially underexpressed genes. We observed STAT5A as a likely putative target gene for miR-650 in aggressive poorly differentiated BRCA. Samples with both Amp-650 and low expression of STAT5A had less overall survival than samples with either or none of the alterations. No target gene has been described for miR-650 in BRCA, thus, this bioinformatic study provides valuable information that should be corroborated experimentally. Full article
(This article belongs to the Special Issue MicroRNA as Biomarkers in Cancer Diagnostics and Therapeutics (II))
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22 pages, 2800 KiB  
Article
Role of miR-30a-3p Regulation of Oncogenic Targets in Pancreatic Ductal Adenocarcinoma Pathogenesis
by Hiroki Shimomura, Reona Okada, Takako Tanaka, Yuto Hozaka, Masumi Wada, Shogo Moriya, Tetsuya Idichi, Yoshiaki Kita, Hiroshi Kurahara, Takao Ohtsuka and Naohiko Seki
Int. J. Mol. Sci. 2020, 21(18), 6459; https://doi.org/10.3390/ijms21186459 - 4 Sep 2020
Cited by 13 | Viewed by 2757
Abstract
Our recent studies have implicated some passenger strands of miRNAs in the molecular pathogenesis of human cancers. Analysis of the microRNA (miRNA) expression signature in pancreatic ductal adenocarcinoma (PDAC) has shown that levels of miR-30a-3p, the passenger strand derived from pre-mir-30a, are significantly [...] Read more.
Our recent studies have implicated some passenger strands of miRNAs in the molecular pathogenesis of human cancers. Analysis of the microRNA (miRNA) expression signature in pancreatic ductal adenocarcinoma (PDAC) has shown that levels of miR-30a-3p, the passenger strand derived from pre-mir-30a, are significantly downregulated in PDAC tissues. This study aimed to identify the oncogenes closely involved in PDAC molecular pathogenesis under the regulation of miR-30a-3p. Ectopic expression assays showed that miR-30a-3p expression inhibited the aggressiveness of the PDAC cells, suggesting that miR-30a-3p acts as a tumor-suppressive miRNA in PDAC cells. We further identified 102 putative targets of miR-30a-3p regulation in PDAC cells by combining in silico analysis with gene expression data. Of these, ten genes (EPS8, HMGA2, ENDOD1, SLC39A10, TGM2, MGLL, SERPINE1, ITGA2, DTL, and UACA) were independent prognostic factors in multivariate analysis of survival of patients with PDAC (p < 0.01). We also investigated the oncogenic function of the integrin ITGA2 in PDAC cell lines. The integrin family comprises cell adhesion molecules expressed as heterodimeric, transmembrane proteins on the surface of various cells. Overexpression of ITGA2/ITGB1 (an ITGA2 binding partner) was detected in the PDAC clinical specimens. The knockdown of ITGA2 expression attenuated the malignant phenotypes of the PDAC cells. Together, results from these microRNA-based approaches can accelerate our understanding of PDAC molecular pathogenesis. Full article
(This article belongs to the Special Issue MicroRNA as Biomarkers in Cancer Diagnostics and Therapeutics (II))
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19 pages, 2676 KiB  
Article
MiR-93/miR-375: Diagnostic Potential, Aggressiveness Correlation and Common Target Genes in Prostate Cancer
by Ewa Ciszkowicz, Paweł Porzycki, Małgorzata Semik, Ewa Kaznowska and Mirosław Tyrka
Int. J. Mol. Sci. 2020, 21(16), 5667; https://doi.org/10.3390/ijms21165667 - 7 Aug 2020
Cited by 15 | Viewed by 2891
Abstract
Dysregulation of miRNAs has a fundamental role in the initiation, development and progression of prostate cancer (PCa). The potential of miRNA in gene therapy and diagnostic applications is well documented. To further improve miRNAs’ ability to distinguish between PCa and benign prostatic hyperplasia [...] Read more.
Dysregulation of miRNAs has a fundamental role in the initiation, development and progression of prostate cancer (PCa). The potential of miRNA in gene therapy and diagnostic applications is well documented. To further improve miRNAs’ ability to distinguish between PCa and benign prostatic hyperplasia (BPH) patients, nine miRNA (-21, -27b, -93, -141, -205, -221, -182, -375 and let-7a) with the highest reported differentiation power were chosen and for the first time used in comparative studies of serum and prostate tissue samples. Spearman correlations and response operating characteristic (ROC) analyses were applied to assess the capability of the miRNAs present in serum to discriminate between PCa and BPH patients. The present study clearly demonstrates that miR-93 and miR-375 could be taken into consideration as single blood-based non-invasive molecules to distinguish PCa from BPH patients. We indicate that these two miRNAs have six common, PCa-related, target genes (CCND2, MAP3K2, MXI1, PAFAH1B1, YOD1, ZFYVE26) that share the molecular function of protein binding (GO:0005515 term). A high diagnostic value of the new serum derived miR-182 (AUC = 0.881, 95% confidence interval, CI = 0.816–0.946, p < 0.0001, sensitivity and specificity were 85% and 79%, respectively) is also described. Full article
(This article belongs to the Special Issue MicroRNA as Biomarkers in Cancer Diagnostics and Therapeutics (II))
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16 pages, 2532 KiB  
Article
Synergetic Effects of Intronic Mature miR-944 and ΔNp63 Isoforms on Tumorigenesis in a Cervical Cancer Cell Line
by Jungho Kim, Sunyoung Park, Yunhee Chang, Kwang Hwa Park and Hyeyoung Lee
Int. J. Mol. Sci. 2020, 21(16), 5612; https://doi.org/10.3390/ijms21165612 - 5 Aug 2020
Cited by 2 | Viewed by 2789
Abstract
miR-944 is located in an intron of the tumor protein p63 gene (TP63). miR-944 expression levels in cervical cancer tissues are significantly higher than in normal tissues and are associated with tumor size, International Federation of Gynecology and Obstetrics (FIGO) stage, [...] Read more.
miR-944 is located in an intron of the tumor protein p63 gene (TP63). miR-944 expression levels in cervical cancer tissues are significantly higher than in normal tissues and are associated with tumor size, International Federation of Gynecology and Obstetrics (FIGO) stage, lymph node metastasis, and survival. However, associations of miR-944 with its host gene, TP63, which encodes TAp63 and ΔNp63, in cervical cancer have not been fully investigated. A positive correlation between miR-944 and ΔNp63 mRNA expression was identified in cervical cancer tissues. Furthermore, when the expression of miR-944 and ΔNp63 was simultaneously inhibited, cell proliferation-, differentiation- epithelial–mesenchymal transition (EMT)-, transcription-, and virus-associated gene clusters were shown to be significantly more active according to functional annotation analysis. Cell viability and migration were more reduced upon simultaneous inhibition with anti-miR-944 or ΔNp63 siRNA than with inhibition with anti-miR-944 or ΔNp63 siRNA alone, or scramble. In addition, Western blot analysis showed that the simultaneous inhibition of miR-944 and ΔNp63 reduced EMT by increasing the expression of epithelial markers such as claudin and by decreasing mesenchymal markers such as N-cadherin and vimentin. Slug, an EMT transcription factor, was also decreased by the simultaneous inhibition of miR-944 and ΔNp63. Thus, associations between miR-944 and ΔNp63 in cervical cancer could help to elucidate the function of this intronic microRNA and its role in carcinogenesis. Full article
(This article belongs to the Special Issue MicroRNA as Biomarkers in Cancer Diagnostics and Therapeutics (II))
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17 pages, 4151 KiB  
Article
Long Non-Coding RNA HAND2-AS1 Acts as a Tumor Suppressor in High-Grade Serous Ovarian Carcinoma
by Priyanka Gokulnath, Tiziana de Cristofaro, Ichcha Manipur, Tina Di Palma, Amata Amy Soriano, Mario Rosario Guarracino and Mariastella Zannini
Int. J. Mol. Sci. 2020, 21(11), 4059; https://doi.org/10.3390/ijms21114059 - 5 Jun 2020
Cited by 21 | Viewed by 3300
Abstract
Long non-coding RNAs (lncRNAs) are increasingly being identified as crucial regulators in pathologies like cancer. High-grade serous ovarian carcinoma (HGSC) is the most common subtype of ovarian cancer (OC), one of the most lethal gynecological malignancies. LncRNAs, especially in cancers such as HGSC, [...] Read more.
Long non-coding RNAs (lncRNAs) are increasingly being identified as crucial regulators in pathologies like cancer. High-grade serous ovarian carcinoma (HGSC) is the most common subtype of ovarian cancer (OC), one of the most lethal gynecological malignancies. LncRNAs, especially in cancers such as HGSC, could play a valuable role in diagnosis and even therapy. From RNA-sequencing analysis performed between an OC cell line, SKOV3, and a Fallopian Tube (FT) cell line, FT194, an important long non-coding RNA, HAND2 Anti sense RNA 1 (HAND2-AS1), was observed to be significantly downregulated in OCs when compared to FT. Its downregulation in HGSC was validated in different datasets and in a panel of HGSC cell lines. Furthermore, this study shows that the downregulation of HAND2-AS1 is caused by promoter hypermethylation in HGSC and behaves as a tumor suppressor in HGSC cell lines. Since therapeutic relevance is of key importance in HGSC research, for the first time, HAND2-AS1 upregulation was demonstrated to be one of the mechanisms through which HDAC inhibitor Panobinostat could be used in a strategy to increase HGSC cells’ sensitivity to chemotherapeutic agents currently used in clinical trials. To unravel the mechanism by which HAND2-AS1 exerts its role, an in silico mRNA network was constructed using mRNAs whose expressions were positively and negatively correlated with this lncRNA in HGSC. Finally, a putative ceRNA network with possible miRNA targets of HAND2-AS1 and their mRNA targets was constructed, and the enriched Gene Ontology (GO) biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified. Full article
(This article belongs to the Special Issue MicroRNA as Biomarkers in Cancer Diagnostics and Therapeutics (II))
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Review

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33 pages, 1316 KiB  
Review
MicroRNAs as Guardians of the Prostate: Those Who Stand before Cancer. What Do We Really Know about the Role of microRNAs in Prostate Biology?
by Thomas Andl, Kavya Ganapathy, Alexia Bossan and Ratna Chakrabarti
Int. J. Mol. Sci. 2020, 21(13), 4796; https://doi.org/10.3390/ijms21134796 - 7 Jul 2020
Cited by 13 | Viewed by 3246
Abstract
Prostate cancer is the second leading cause of cancer-related deaths of men in the Western world. Despite recent advancement in genomics, transcriptomics and proteomics to understand prostate cancer biology and disease progression, castration resistant metastatic prostate cancer remains a major clinical challenge and [...] Read more.
Prostate cancer is the second leading cause of cancer-related deaths of men in the Western world. Despite recent advancement in genomics, transcriptomics and proteomics to understand prostate cancer biology and disease progression, castration resistant metastatic prostate cancer remains a major clinical challenge and often becomes incurable. MicroRNAs (miRNAs), about 22-nucleotide-long non-coding RNAs, are a group of regulatory molecules that mainly work through post-transcriptional gene silencing via translational repression. Expression analysis studies have revealed that miRNAs are aberrantly expressed in cancers and have been recognized as regulators of prostate cancer progression. In this critical review, we provide an analysis of reported miRNA functions and conflicting studies as they relate to expression levels of specific miRNAs and prostate cancer progression; oncogenic and/or tumor suppressor roles; androgen receptor signaling; epithelial plasticity; and the current status of diagnostic and therapeutic applications. This review focuses on select miRNAs, highly expressed in normal and cancer tissue, to emphasize the current obstacles faced in utilizing miRNA data for significant impacts on prostate cancer therapeutics. Full article
(This article belongs to the Special Issue MicroRNA as Biomarkers in Cancer Diagnostics and Therapeutics (II))
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