CircPLEKHM3 acts as a tumor suppressor through regulation of the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis in ovarian cancer

作者：Lei Zhang, Qing Zhou, Qiongzi Qiu, Ling Hou, Mengting Wu, Jia Li, Xufan Li, Bingjian Lü, Xiaodong Cheng, Pengyuan Liu, Weiguo Lü, Yan Lü · 发表于：Molecular Cancer · 年份：2019 · DOI：10.1186/s12943-019-1080-5 · 被引用次数：168 · 研究领域：Circular RNAs in diseases、MicroRNA in disease regulation、Cancer-related molecular mechanisms research

BACKGROUND: Emerging evidence has shown that circular RNAs (circRNAs) play essential roles in cancer biology and are potential biomarkers and targets for cancer therapy. However, the expression and function of circRNAs in ovarian carcinogenesis and its progression remain elusive. METHODS: RNA sequencing was performed to reveal circRNA expression profiles in ovarian cancerous and normal tissues. Single-molecule RNA in-situ hybridization was used to quantify circPLEKHM3 expression in tumor tissues. Cell-based in-vitro and in-vivo assays were subsequently conducted to support the clinical findings. RESULTS: CircPLEKHM3 was identified as one of the most significantly down-regulated circRNAs in ovarian cancer tissues compared with normal tissues. Its expression was further decreased in peritoneal metastatic ovarian carcinomas compared to primary ovarian carcinomas. Patients with lower circPLEKHM3 tend to have a worse prognosis. Functionally, circPLEKHM3 overexpression inhibited cell growth, migration and epithelial-mesenchymal transition, whereas its knockdown exerted an opposite role. Further analyses showed that circPLEKHM3 sponged miR-9 to regulate the endogenous expression of BRCA1, DNAJB6 and KLF4, and consequently inactivate AKT1 signaling. In addition, AKT inhibitor MK-2206 could block the tumor-promoting effect of circPLEKHM3 depletion, and potentiate Taxol-induced growth inhibition of ovarian cancer cells. CONCLUSIONS: Our findings demonstrated that circPLEKHM3 functions ...