MiR-596 activated by EP300 controls the tumorigenesis in epithelial ovarian cancer by declining BRD4 and KPNA4
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PRIMARY RESEARCH
Cancer Cell International Open Access
MiR‑596 activated by EP300 controls the tumorigenesis in epithelial ovarian cancer by declining BRD4 and KPNA4 Deying Wang, Yulan Cui, Aili Xu, Lin Zhao and Peiling Li*
Abstract Background: Epithelial ovarian cancer (EOC), a subclass of ovarian cancer (OC), is usually diagnosed at advanced stages due to the lack of effective screening means. Mounting reports have disclosed the vitally important roles of microRNAs (miRNAs) in carcinogenesis. Here, we aimed to find out possible miRNAs participating in EOC development. Methods: qRT-PCR ad western blot respectively examined the mRNA and protein levels of studied genes. CCK-8, colony formation, flow cytometry, TUNEL and spheroid formation assays were appropriately employed for examining cell proliferation, cell cycle, apoptosis and stemness. The interaction between molecules was affirmed by luciferase reporter, RNA pull down and ChIP assays. Results: In consistent with the observation of a past study, miR-596 expression was relatively low in EOC cells. Upregulating miR-596 suppressed EOC cell proliferation and stemness. EP300 transcriptionally activated miR-596 to serve as a tumor-repressor in EOC. Then BRD4 and KPNA4, whose knockdown led to restraining effects on cell growth and stemness, were both revealed to be targeted by miR-596 in EOC. Lastly, rescue assays affirmed the tumor-restraining role of miR-596-BRD4/KPNA4 axis in EOC. Conclusion: EP300-activated miR-596 hampered cell growth and stemness via targeting BRD4 and KPNA4 in EOC, proofing miR-596 as a promising therapeutic target in treating EOC patients. Keywords: Epithelial ovarian cancer (EOC), EP300, miR-596, BRD4, KPNA4 Background Ovarian cancer (OC) is a deadly carcinoma in gynecological system [1, 2], among which epithelial ovarian cancer (EOC) is a typical subclass with the most mortality [3]. Owing to the lack of early symptoms and valid biomarkers, EOC patients often develop into advanced stages when diagnosed, which finally results in disappointing prognosis [4]. Therefore, the identification of available biomarkers for treating EOC patients is the urgent task. *Correspondence: [email protected] Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Harbin Medical University, No. 246, Xuefu Road, Nangang District, Harbin, China
Unlike long noncoding RNAs (lncRNAs), microRNAs (miRs) are noncoding RNAs (ncRNAs) with approximately 20 nt in length [5, 6]. They are widely known to recognize specific sequences in the 3′UTR of target message RNAs (mRNAs) to induce the silence of these mRNAs, so as to elicit restraining or facilitating roles in carcinomas [7]. Moreover, miRNAs with abnormal expression have been proved to affect cellular activities in diverse human cancers [8, 9]. For examples, circRNA AGFG1 acts as a sponge of miR-195-5p to promote triple-negative breast cancer progression through regulating CCNE1 expression [10]; miR-760 suppresses human colorectal cancer cell growth by targeting BATF3AP-1/ cyclinD1 signaling [1
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