CircPLEKHM3 acts as a tumor suppressor through regulation of the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis in ovarian cancer
CircPLEKHM3 acts as a tumor suppressor through regulation of the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis in ovarian cancer
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CircPLEKHM3 通过调节卵巢癌中的 miR-9/BRCA1/DNAJB6/KLF4/AKT1 轴发挥肿瘤抑制因子的作用
DOI：
10.1186/s12943-019-1080-5
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发表时间：
2019-10-17
期刊：
影响因子：
37.3
通讯作者：
Lu, Yan
中科院分区：
文献类型：
--
作者：
Zhang, Lei;Zhou, Qing;Lu, Yan
研究背景环状RNA（circular RNA，circRNA）在肿瘤生物学中起重要作用，是潜在的肿瘤生物标志物和治疗靶点。然而，circRNA的表达和功能在卵巢癌的发生和发展仍然habitued.MethodsRNA测序揭示circRNA在卵巢癌和正常组织中的表达谱。单分子RNA原位杂交用于定量肿瘤组织中的circPLEKHM 3表达。结果CircPLEKHM 3在卵巢癌组织中的表达较正常卵巢组织明显下调，在卵巢癌组织中的表达与正常卵巢组织相比差异有统计学意义。与原发性卵巢癌相比，其表达在腹膜转移性卵巢癌中进一步降低。circPLEKHM 3较低的患者往往预后较差。在功能上，circPLEKHM 3过表达抑制细胞生长，迁移和上皮-间质转化，而其敲低发挥相反的作用。进一步的分析表明，circPLEKHM 3吸收miR-9来调节BRCA 1、DNAJB 6和KLF 4的内源性表达，从而调节BRCAKT 1信号传导。此外，AKT抑制剂MK-2206可阻断circPLEKHM 3耗竭的促肿瘤作用，并增强紫杉醇诱导的卵巢癌细胞生长抑制作用。结论circPLEKHM 3通过靶向miR-9/BRCA 1/DNAJB 6/KLF 4/AKT 1轴在卵巢癌细胞中发挥抑癌作用，可作为卵巢癌患者的预后指标和治疗靶点。紫杉醇与MK-2206联合治疗卵巢癌的新策略值得进一步研究，特别是在circPLEKHM 3表达缺失的卵巢癌患者中。
BackgroundEmerging 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.MethodsRNA 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.ResultsCircPLEKHM3 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.ConclusionsOur findings demonstrated that circPLEKHM3 functions as a tumor suppressor in ovarian cancer cells by targeting the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis and may be used as a prognostic indicator and therapeutic target in ovarian cancer patients. The new strategy for treating ovarian cancer by a combination therapy of Taxol with MK-2206 is worth further investigation, especially in ovarian cancer patients with loss of circPLEKHM3 expression.