Comprehensive analysis of microRNAs and their target genes in oral submucous fibrosis.

The objective of the study is to understand the role of experimentally validated microRNAs (miRNAs) contributing to the acquisition of oncogenic phenotype in oral submucous fibrosis (OSF) by computational analysis. A comprehensive review was carried out to corroborate and summarize altered miRNA expression in OSF by retrieving relevant publications querying MEDLINE, Web of Science, Embase, and Scopus. The association between the miRNA-mRNA was performed using miRTarBase 8.0. The visualization of the miRNA-mRNA interaction was plotted using Cytoscape. MIENTURNET was used for the pathway analysis. Enrichment analysis was carried out for elucidating the hierarchical functions of miRNAs related to the acquisition of biological processes involved in the development of cancer. Thirteen miRNAs (hsa-miR-499a, hsa-miR-200b, hsa-miR-200c, hsa-miR-1246, hsa-miR-31, hsa-miR-10b, hsa-miR-21, hsa-miR-203, hsa-miR-455, hsa-miR-760, hsa-miR-623, hsa-miR-610, and hsa-miR-509-3-5p) were found to be deregulated in OSF. A total of 371 experimentally validated genes were shown to be interacting with the OSF-associated miRNAs. The targets of antifibrotic and profibrotic miRNAs were enriched in the cancer-related pathways. Dysregulated miRNA and its target genes illustrate the physiological role of miRNAs in fibrosis. Understanding the miRNA-mediated fibrotic signaling and targetting the specific miRNA-target gene interaction might provide relevant cues to ameliorate the fibrotic disease.

Increased expression of P-cadherin is an indicator of poor prognosis in breast cancer: a systematic review and meta-analysis.

PURPOSE: P-cadherin (CDH3), located at 16q22.1 belonging to classical cadherin family, is a calcium-dependent glycoprotein associated with cell to cell adhesion, migration, and invasion in cancer. This meta-analysis was conducted to examine the prognostic utility of P-cadherin expression in breast cancer (BC). METHODS: A comprehensive literature search was carried out using the available databases to obtain relevant research articles to test the relationship between P-cadherin and BC. Correlation of P-cadherin expression and disease-free survival (DFS) or overall survival (OS) was tested using hazard ratio (HR), relative risk (RR) at 95% confidence interval (CI) by univariate and/or multivariate analysis. A total of 11 studies from 7 countries were found to be relevant and were further subjected to statistical analysis to find an association between the P-cadherin expression with BC. Additionally, we have also performed a co-relation analysis of P-cadherin expression with GOBO and Cancertool in breast cancer using publicly available breast cancer datasets. RESULTS: Our study shows that P-cadherin expression is significantly linked with poor prognosis in the various subtypes of BC. The HR for OS and DFS was 1.87 (95% CI = 1.48-2.36) and 1.64 (95% CI = 1.18-2.27) respectively. CONCLUSIONS: In this meta-analysis, we identified a positive correlation between the overexpression of P-cadherin and BC. Our study demonstrates that P-cadherin overexpression can be used as a prognostic indicator in BC.

Regulation and tumor-suppressive function of the miR-379/miR-656 (C14MC) cluster in cervical cancer.

Cervical cancer (CC) is a key contributor to cancer-related mortality in several countries. The identification of molecular markers and the underlying mechanism may help improve CC management. We studied the regulation and biological function of the chromosome 14 microRNA cluster (C14MC; miR-379/miR-656) in CC. Most C14MC members exhibited considerably lower expression in CC tissues and cell lines in The Cancer Genome Atlas (TCGA) cervical squamous cell carcinoma and endocervical adenocarcinoma patient cohorts. Bisulfite Sanger sequencing revealed hypermethylation of the C14MC promoter in CC tissues and cell lines. 5-aza-2 deoxy cytidine treatment reactivated expression of the C14MC members. We demonstrated that C14MC is a methylation-regulated miRNA cluster via artificial methylation and luciferase reporter assays. C14MC downregulation correlated with poor overall survival and may promote metastasis. C14MC activation via the lentiviral-based CRISPRa approach inhibited growth, proliferation, migration, and invasion; enhanced G2/M arrest; and induced senescence. Post-transcriptional regulatory network analysis of C14MC transcriptomic data revealed enrichment of key cancer-related pathways, such as metabolism, the cell cycle, and phosphatidylinositol 3-kinase (PI3K)-AKT signaling. Reduced cell proliferation, growth, migration, invasion, and senescence correlated with the downregulation of active AKT, MYC, and cyclin E1 (CCNE1) and the overexpression of p16, p21, and p27. We showed that C14MC miRNA activation increases reactive oxygen species (ROS) levels, intracellular Ca2+ levels, and lipid peroxidation rates, and inhibits epithelial-mesenchymal transition (EMT). C14MC targets pyruvate dehydrogenase kinase-3 (PDK3) according to the luciferase reporter assay. PDK3 is overexpressed in CC and is inversely correlated with C14MC. Both miR-494-mimic transfection and C14MC activation inhibited PDK3 expression. Reduced glucose uptake and lactate production, and upregulation of PDK3 upon C14MC activation suggest the potential role of these proteins in metabolic reprogramming. Finally, we showed that C14MC activation may inhibit EMT signaling. Thus, C14MC is a tumor-suppressive and methylation-regulated miRNA cluster in CC. Reactivation of C14MC can be useful in the management of CC.

Nanoparticulate strategies for the delivery of miRNA mimics and inhibitors in anticancer therapy and its potential utility in oral submucous fibrosis.

MicroRNAs (miRNAs) are naturally occurring noncoding RNAs with multiple functionalities. They are dysregulated in several conditions and can serve as disease biomarkers, therapeutic targets and therapeutic agents. Translation of miRNA therapeutics to the clinic poses several challenges related to the safe and effective delivery of these agents to the site of action. Nanoparticulate carriers hold promise in this area by enhancing targeting efficiency and reducing off-target effects. This paper reviews recent advances in the delivery strategies of miRNAs in anticancer therapy, with a focus on lipid-based, polymeric, inorganic platforms, cell membrane-derived vesicles and bacterial minicells. Additionally, this review explores the potentiality of miRNAs in the treatment of oral submucous fibrosis, a potentially premalignant condition of the oral cavity with no definitive treatment to date.

Prognostic Value of Melanoma-Associated Antigen-A (MAGE-A) Gene Expression in Various Human Cancers: A Systematic Review and Meta-analysis of 7428 Patients and 44 Studies.

BACKGROUND: Members of the melanoma-associated antigen-A (MAGE-A) subfamily are overexpressed in many cancers and can drive cancer progression, metastasis, and therapeutic recurrence. OBJECTIVE: This study is the first comprehensive meta-analysis evaluating the prognostic utility of MAGE-A members in different cancers. METHODS: A systematic literature search was conducted in PubMed, Google Scholar, Science Direct, and Web of Science. The pooled hazard ratios with 95% confidence intervals were estimated to evaluate the prognostic significance of MAGE-A expression in various cancers. RESULTS: In total, 44 eligible studies consisting of 7428 patients from 11 countries were analysed. Univariate and multivariate analysis for overall survival, progression-free survival, and disease-free survival showed a significant association between high MAGE-A expression and various cancers (P < 0.00001). Additionally, subgroup analysis demonstrated that high MAGE-A expression was significantly associated with poor prognosis for lung, gastrointestinal, breast, and ovarian cancer in both univariate and multivariate analysis for overall survival. CONCLUSION: Overexpression of MAGE-A subfamily members is linked to poor prognosis in multiple cancers. Therefore, it could serve as a potential prognostic marker of poor prognosis in cancers.

Role of miRNA clusters in epithelial to mesenchymal transition in cancer.

Epithelial to mesenchymal transition (EMT) is a multistep biological process in which epithelial cells acquire characteristics of mesenchymal cells. Inappropriate activation of EMT contributes to the acquisition of pro-metastatic characteristics and cancer progression. EMT process involves the downregulation of epithelial markers (EpCAM, CDH1) and upregulation of mesenchymal markers (VIM, CDH2) and EMT-transcription factors (ZEB1/2, TWIST1/2, SNAI1, SLUG). MicroRNAs, a class of non-coding RNA post-transcriptionally govern gene expression by binding to the target mRNAs. A large proportion of miRNAs occur as miRNA clusters consisting of two or more miRNA coding genes. MiRNA clusters are reported to regulate diverse biological functions, including EMT. This comprehensive review discusses the role of miRNA clusters in EMT.

Prognostic role of 14q32.31 miRNA cluster in various carcinomas: a systematic review and meta-analysis.

Deregulated miR-379/miR-656 cluster expression is considered as important for carcinogenesis and can be used as a potential prognostic marker. Hence, the meta-analysis was conducted to test the utility of miR-379/miR-656 cluster as a prognostic marker in various cancers. A literature search was performed using Web of Science, PubMed and Cochrane Library to obtain relevant studies and were subjected to various subgroup and bioinformatics analyses. Selected twenty-three studies contained 13 cancer types comprising of 3294 patients from 7 nations. Univariate and multivariate data showed an association of high expression of miRNAs with the poor prognosis of cancer patients (p < 0.001). The subgroup analysis showed that lung cancer, breast cancer and papillary renal cell carcinoma (p < 0.001) have a negative association with the survival of patients. Our study is the first meta-analysis showing the association of miR-379/miR-656 cluster expression and overall survival, suggesting its potential as a prognostic indicator in multiple cancers.

Characterizing methylation regulated miRNA in carcinoma of the human uterine cervix.

Gene regulatory mechanisms determine the multistep carcinogenesis process. Two aspects of epigenetics are microRNA (miRNAs) and DNA methylation that regulate distinct biological mechanisms such as metastasis, apoptosis cell proliferation and induction of senescence. Although critical, the interplay between these two epigenetic mechanisms is yet to be completely understood, particularly in cervical cancer. To study the DNA methylation regulation of miRNAs and its potential role in cervical cancer, we investigated the differential methylation pattern of two candidate miRNAs (miR-375 and miR-196a-1) during cervical cancer progression against normal cervical epithelium (NCE) by bisulfite DNA sequencing. miR-375 and miR-196a-1 were hypermethylated in Squamous Cell Carcinoma (SCC) against NCE and Cervical Intra-Epithelial Neoplasia (CIN) (p < 0.05). Treatment with demethylating agent reactivated the miR-375 and miR-196a-1 expression in SiHa, HeLa and CaSki cells. In vitro artificial methylation by M.SssI followed by dual luciferase assay confirmed miR-375 and miR-196a-1 as methylation regulated miRNAs (P < 0.05). miR-375 and miR-196a-1 expression levels were negatively correlated with methylation levels in clinical specimens. We further identified Replication Factor C Subunit 3 (RFC3) and High Mobility Group AT-Hook 1 (HMGA1) as targets of miR-375 and miR-196a-1 respectively by dual luciferase reporter assay. Our analysis indicates that miR-375 and miR-196a-1 are DNA methylation regulated miRNAs whose deregulation may facilitate pathophysiology of cervical cancer.