miR‑377 targets CUL4A and regulates metastatic capability in ovarian cancer

Abstract

Abstract. The incidence and recurrence rates of ovarian cancer are still high, and once the disease metastasizes, it is nearly always fatal. Cullin 4A (CUL4A) serves a significant role in tumourigenesis and tumour progression; however, the effect and mechanisms underlying cUL4A overexpression are still unknown. The role of microRNAs (miRs) in the regulation of metastatic capability in ovarian cancer cell lines was investigated. The interaction between miR-377 and cUL4A was investigated using bioinformatics analyses and dual-luciferase reporter assays. Furthermore, miR-377 mRNA and protein levels were detected using reverse transcription-quantitative polymerase chain reaction and western blotting, respectively and cell migration and invasion were detected using a Transwell assay. Results revealed that cUL4A expression was negatively associated with miR-377 levels in ovarian cancer tissues and cell lines. Through in silico analysis, the targeting effect of miR-377 on CUL4A was verified. Ectopic expression of miR-377 in SKOV3 cells downregulated the level of cUL4A, and significantly reduced the migratory ability of the cells. miR-377 overexpression led to reduced activity of the Wnt/β-catenin signaling pathway, and regulated the expression of matrix metalloproteinase-2, and 9, and epithelial-mesenchymal transition (EMT)-associated protein.These results suggested that miR-377 is a significant negative regulator of cUL4A that controls cancer cell progression in ovarian cancer cell lines. IntroductionAccording to a previous study, ovarian cancer still remains the fifth-leading cause of mortality in women, with approximately 22,280 newly diagnosed cases and 14,240 mortalities reported in 2016 worldwide (1). With such a high recurrence rate, over three quarters of ovarian cancer patients eventually relapse following primary platinum and taxane-based chemotherapy (2). development of cytotoxic chemotherapy and novel targeted therapies have enhanced progression-free survival, however failed to have significant influence on overall survival (3,4). Malignant tumours, including ovarian cancer, are characterized by tumour metastasis from the primary site to other parts via the lymphatic system, blood vessels, or body cavity (5). To better understand the underlying molecular mechanism of carcinogenesis in order to develop more effective therapeutic strategies, more research studies need to be conducted.Previously, the use of miRNAs as a novel effective target in cancer therapy has been extensively reported (6-10). miRNAs are small non-coding RNA molecules with a length varying from 19-25 nt. Previous studies have demonstrated that miRNAs that are generated in cells serve important roles in a variety of biological processes; in particular, they negatively regulate gene expression following transcription. A mature miRNA chain is able to combine with the 3' untranslated region (UTR) of target mRNA in an RNA-induced silencing complex; in this way, complete complementary miRNA and target mRNA result in inhibition or activation of tr...

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