Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510315, China; Southern Medical University, Guangzhou, 510000, China.
Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China.
Biomed Pharmacother. 2020 May;125:109865. doi: 10.1016/j.biopha.2020.109865. Epub 2020 Feb 12.
The pathogenesis of ovarian cancer remains to be elucidated. Our previous study demonstrated that myosin heavy chain 9 (MYH9) overexpression was associated with poor prognosis of epithelial ovarian cancer. However, the mechanism of MYH9 and its regulation by microRNA (miR) is not clear. The results of the present study demonstrated that miR-6089 was one of the microRNAs targeting MYH9, and miR-6089 overexpression suppressed ovarian cancer cell proliferation, migration, invasion and metastasis in vivo and in vitro. Mechanistic studies confirmed that miR-6089 directly targeted MYH9 to inactivate the Wnt/β-catenin signalling pathway and its downstream epithelial-to-mesenchymal transition (EMT), cell-cycle factors and c-Jun, whereas overexpression of MYH9 reversed the inhibitory effects of miR-6089 overexpression in ovarian cancer cells by upregulating the Wnt/β-catenin and its downstream EMT, cell-cycle factors and c-Jun. Interestingly, miR-6089 was transcriptionally inhibited by c-Jun, a transcription factor which could be induced by MYH9 via the Wnt/β-catenin pathway. Thus miR-6089/MYH9/β-catenin/c-Jun formed a negative feedback loop in ovarian cancer. In clinical samples, miR-6089 negatively correlated with MYH9 expression. Our study is the first to demonstrate that miR-6089 serves as a tumor-suppressive miRNA, and miR-6089/MYH9/β-catenin/c-Jun negative feedback loop inhibits ovarian cancer carcinogenesis and progression.
卵巢癌的发病机制仍有待阐明。我们之前的研究表明，肌球蛋白重链 9 (MYH9) 过表达与上皮性卵巢癌的预后不良有关。然而，MYH9 的机制及其受 microRNA (miR) 的调控尚不清楚。本研究结果表明，miR-6089 是靶向 MYH9 的 microRNAs 之一，miR-6089 过表达抑制卵巢癌细胞在体内和体外的增殖、迁移、侵袭和转移。机制研究证实，miR-6089 可直接靶向 MYH9 以灭活 Wnt/β-catenin 信号通路及其下游上皮间质转化（EMT）、细胞周期因子和 c-Jun，而过表达 MYH9 则通过上调 Wnt/β-catenin 及其下游 EMT、细胞周期因子和 c-Jun，逆转 miR-6089 过表达对卵巢癌细胞的抑制作用。有趣的是，miR-6089 被转录因子 c-Jun 转录抑制，c-Jun 可通过 Wnt/β-catenin 途径被 MYH9 诱导。因此，miR-6089/MYH9/β-catenin/c-Jun 在卵巢癌中形成负反馈环。在临床样本中，miR-6089 与 MYH9 的表达呈负相关。本研究首次证明 miR-6089 作为一种肿瘤抑制性 miRNA，miR-6089/MYH9/β-catenin/c-Jun 负反馈环抑制卵巢癌的发生和发展。
