miR-218 suppresses gastric cancer cell cycle progression through the CDK6/Cyclin D1/E2F1 axis in a feedback loop
miR-218 suppresses gastric cancer cell cycle progression through the CDK6/Cyclin D1/E2F1 axis in a feedback loop
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miR-218 通过反馈环路中的 CDK6/Cyclin D1/E2F1 轴抑制胃癌细胞周期进程
DOI：
10.1016/j.canlet.2017.06.006
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发表时间：
2017-09-10
期刊：
影响因子：
9.7
通讯作者：
He, Zhimin
中科院分区：
文献类型：
--
作者：
Deng, Min;Zeng, Chao;He, Zhimin
在几种癌症中的研究表明，miR-218具有抗肿瘤活性，但其功能尚未阐明。本研究旨在探讨miR-218- 5 p在胃癌细胞周期进程中的调控作用。我们发现miR-218在体内可以抑制胃癌细胞的增殖，诱导细胞周期阻滞在G1期，抑制肿瘤的生长和转移。我们还证明了miR-218特异性靶向CDK 6和cyclin D1的3 '-UTR区域，并抑制这些分子的表达，这反过来又抑制了pRb/E2 F1信号通路。CDK 6和Cyclin Dl的过表达逆转了miR-218介导的pRI 3/E2 F1信号转导抑制，并减弱了miR-218诱导的细胞周期停滞。更重要的是，胃癌组织中miR-218的表达显著降低，并且与CDK 6和Cyclin D1的水平呈负相关。胃癌患者中miR-218表达降低与临床分期、淋巴结转移和预后不良相关。此外，我们发现E2 F1通过miR-218宿主基因SLIT 2和SLIT 3的反式激活直接激活miR-218表达，揭示了miR-218表达的负反馈调节。综上所述，我们的研究结果描述了一个调控环miR-218-CDK 6/CyclinD 1-E2 F1，其破坏可能有助于胃癌细胞周期的进展，并表明miR-218在癌症治疗中的潜在应用。(C)2017爱思唯尔B. V.保留所有权利。
Studies in several cancers have suggested that miR-218 has anti-tumor activities, but its function is yet to be elucidated. In this study, we investigated the regulation and function of miR-218 (miR-218-5p) in the cell cycle progression of gastric cancer (GC). We found that miR-218 could suppress proliferation of gastric cancer cells, induce cell cycle arrest at the G1 phase and inhibit tumor growth and metastasis in vivo. We also demonstrated that miR-218 specifically targeted the 3'-UTR regions of CDK6 and cyclin D1 and inhibited the expression of these molecules, which in turn repressed the pRb/E2F1 signaling pathway. Overexpression of CDK6 and Cyclin Dl reversed miR-218-mediated inhibition of pRI3/E2F1 signaling and attenuated the miR-218-induced cell cycle arrest. More importantly, miR-218 expression was significantly reduced and inversely correlated with the levels of CDK6 and Cyclin Dl in gastric cancer tissues. Decreased miR-218 expression was also correlated with advanced clinical stage, lymph node metastasis, and poor prognosis in gastric cancer patients. Furthermore, we showed that miR-218 expression was directly activated by E2F1 through the transactivation of miR-218 host genes, SLIT2 and SLIT3, revealing a negative feedback regulation of miR-218 expression. Taken together, our results describe a regulatory loop miR-218-CDK6/CyclinD1-E2F1 whose disruption may contribute to cell cycle progression in gastric cancer and indicate the potential application of miR-218 in cancer therapy. (C) 2017 Elsevier B.V. All rights reserved.