The Role of miR-590-3p in Regulating Human Epithelial Ovarian Cancer Development
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Epithelial ovarian cancer (EOC) has the highest mortality rate among all gynecological malignancies. Early detection and intervention remain key to patient prognosis fueling the search for reliable biomarkers. MicroRNAs (miRNAs) are small non-coding RNAs that play a crucial regulatory role within the cell and their dysregulation is associated with many diseases including cancer. In this study, using several well-characterized human EOC cells lines, EOC patient tissue and serum samples, and an in vivo mouse model we investigated the role and mechanism of miR-590-3p in promoting ovarian cancer. Our findings indicate that miR-590-3p levels were elevated in both clinical ovarian tumor samples, as well as in the blood serum of the same patients than in subjects with benign gynecological disorders. Overexpression of miR-590-3p in multiple EOC cells led to an increase in cell proliferation, migration, invasion, colony formation, and spheroid formation. In addition, injection of cells overexpressing mir-590 precursor into nude mice increased the dissemination of the tumor nodules, and formed larger tumors compared to control groups. cDNA microarray for cells overexpressing mir-590 revealed Forkhead box A2 (FOXA2) and Versican (VCAN) as one of the top downregulated and upregulated genes, respectively. Interestingly, ChIP-qPCR revealed that FOXA2 binds to VCAN promoter, and overexpression of FOXA2 reduced, while knockout of FOXA2 increased, VCAN mRNA and protein levels. Moreover, luciferase assay confirmed that miR-590-3p is directly targeting the 3UTR of FOXA2 and cyclin G2 (CCNG2) to suppress their expressions. In addition, silencing of CCNG2 mimicked the effect of miR-590-3p and induced cell proliferation, migration and invasion, while CCNG2 overexpression reversed this phenotype. In addition, mir-590 precursor increased the -catenin activity in TOPflash assays, whereas, knockdown of -catenin blocks the effect of mir-590 on spheroid formation. Altogether, our results demonstrate that miR-590-3p has tumor-promoting effects in EOCs via targeting FOXA2 and CCNG2 which leads to induction of VCAN and -catenin signaling.