Deng Min, Zeng Chao, Lu Xihong, He Xiusheng, Zhang Ruixin, Qiu Qinwei, Zheng Guopei, Jia Xiaoting, Liu Hao, He Zhimin
Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, Guangdong Province, China.
Department of Pathology, Guangdong Medical University, Dongguan, Guangdong Province, China.
Cancer Lett. 2017 Sep 10;403:175-185. doi: 10.1016/j.canlet.2017.06.006. Epub 2017 Jun 17.
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 D1 reversed miR-218-mediated inhibition of pRB/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 D1 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.
多项癌症研究表明，miR-218具有抗肿瘤活性，但其功能尚待阐明。在本研究中，我们调查了miR-218（miR-218-5p）在胃癌（GC）细胞周期进程中的调控作用及功能。我们发现miR-218可抑制胃癌细胞增殖，诱导细胞周期停滞于G1期，并在体内抑制肿瘤生长和转移。我们还证明，miR-218特异性靶向CDK6和细胞周期蛋白D1的3'-UTR区域，并抑制这些分子的表达，进而抑制pRb/E2F1信号通路。CDK6和细胞周期蛋白D1的过表达逆转了miR-218介导的对pRB/E2F1信号的抑制，并减弱了miR-218诱导的细胞周期停滞。更重要的是，miR-218在胃癌组织中的表达显著降低，且与CDK6和细胞周期蛋白D1的水平呈负相关。miR-218表达降低还与胃癌患者的临床晚期、淋巴结转移及预后不良相关。此外，我们发现E2F1通过对miR-218宿主基因SLIT2和SLIT3的反式激活直接激活miR-218表达，揭示了miR-218表达的负反馈调节机制。综上所述，我们的研究结果描述了一个miR-218-CDK6/细胞周期蛋白D1-E2F1调控环，其破坏可能促进胃癌细胞周期进程，并提示miR-218在癌症治疗中的潜在应用价值。
