miR-6089/MYH9/β-catenin/c-Jun negative feedback loop inhibits ovarian cancer carcinogenesis and progression
miR-6089/MYH9/β-catenin/c-Jun negative feedback loop inhibits ovarian cancer carcinogenesis and progression
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DOI：
10.1016/j.biopha.2020.109865
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发表时间：
2020-05-01
影响因子：
7.5
通讯作者：
Zeng, Zhaoyang
中科院分区：
文献类型：
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作者：
Liu, Longyang;Ning, Yingxia;Zeng, Zhaoyang
卵巢癌的发病机制仍有待阐明。我们的前期研究表明肌球蛋白重链9（MYH 9）过表达与上皮性卵巢癌预后不良相关。然而，MYH 9的机制及其通过microRNA（miR）的调控尚不清楚。本研究结果表明，miR-6089是靶向MYH 9的microRNA之一，miR-6089过表达可抑制卵巢癌细胞的增殖、迁移、侵袭和转移。机制研究证实，miR-6089直接靶向MYH 9以抑制Wnt/β-catenin信号通路及其下游上皮-间充质转化（EMT）、细胞周期因子和c-Jun，而MYH 9的过表达通过上调Wnt/β-catenin及其下游EMT、细胞周期因子和c-Jun来逆转miR-6089过表达在卵巢癌细胞中的抑制作用。miR-6089被c-Jun转录抑制，c-Jun是一种可以通过Wnt/β-连环蛋白途径被MYH 9诱导的转录因子。因此，miR-6089/MYH 9/beta-catenin/c-Jun在卵巢癌中形成负反馈环。在临床样本中，miR-6089与MYH 9表达呈负相关。我们的研究首次证明miR-6089是一种肿瘤抑制性miRNA，miR-6089/MYH 9/beta-catenin/c-Jun负反馈环抑制卵巢癌的发生和进展。
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/beta-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/beta-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/beta-catenin pathway. Thus miR-6089/MYH9/beta-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/beta-catenin/c-Jun negative feedback loop inhibits ovarian cancer carcinogenesis and progression.