Metformin Suppresses Invasion and Metastasis of Gastric Cancer Cells by regulating AMPK and YAP Signaling
Metformin Suppresses Invasion and Metastasis of Gastric Cancer Cells by regulating AMPK and YAP Signaling
复制标题
二甲双胍通过调节 AMPK 和 YAP 信号抑制胃癌细胞的侵袭和转移
作者：
张飞雄;苗雨;阮继刚;孟淑萍
背景：胃癌具有增殖活跃、侵袭性强的特点。二甲双胍已被证明在治疗包括胃癌在内的恶性肿瘤方面具有显著的疗效和安全性。到目前为止，二甲双胍的作用机制，特别是与AMPK和YAP信号通路有关的机制尚不清楚。方法：采用免疫组织化学和Western blotting方法检测二甲双胍的亚细胞定位和相关蛋白的表达水平。采用CCK-8法检测胃癌细胞的增殖能力。结果：AMPK信号与YAP信号呈负相关，YAP信号与胃癌组织呈正相关。二甲双胍以时间和剂量依赖的方式抑制SGC7901和BGC23细胞的增殖和转移潜能。二甲双胍治疗后，E-钙粘蛋白表达明显增加，N-钙粘蛋白和波形蛋白表达水平降低。此外，siAMPK介导的基因敲除导致增殖能力增强、细胞迁移和侵袭，这一作用可被二甲双胍部分逆转。此外，siAMPK介导的基因敲除也减弱了二甲双胍对YAP/CYR61/CTGF信号通路的抑制。结论：二甲双胍至少部分地诱导了AMPK信号的激活。这是抑制胃癌细胞侵袭和转移的基础。二甲双胍诱导的AMPK信号的激活参与了YAP信号通路的负向调控。
Background: Gastric cancer is well-characterized by active proliferation and.aggressive invasion. Metformin has been shown to have a remarkable outcome in.both efficacy and safety in the treatment of malignant tumors including gastric cancer..To date, the underlying mechanism of metformin efficiency, especially with respect to.AMPK and YAP signaling pathways, are yet to be elucidated..Methods:Immunohistochemistry and Western blotting were conducted to determine.the subcellular localization and the expression levels of the related proteins. The.CCK-8 assay was performed for the evaluation of proliferation potential of gastric.cancer cells. Wound healing and transwell assay were carried out to assess the gastric.tumor cell invasion and metastasis..Results: The AMPK signaling was negatively associated with while YAP signaling.was positively correlated with gastric cancer tissues. Proliferative as well as.metastatic potential was suppressed by metformin in a time- and dose-dependent.manner in both SGC7901 and BGC23 cells. Moreover, there an apparent increase in.the E-cadherin expression, while a decrease in the expression level of N-cadherin and.vimentin was observed after metformin treatment. Moreover, siAMPK-mediated.knockdown, which was partially reversed by metformin treatment, led to enhanced.proliferative potential, cellular migration, and invasion. Furthermore,siAMPK-mediated knockdown, which was partially reversed by metformin treatment,.also attenuated the metformin-induced suppression of YAP/CYR61/CTGF signaling..Conclusion: Metformin-induced activation of AMPK signaling at least partially.underlies the inhibitory effect on tumor cell invasion and metastasis of gastric cancer..Metformin-induced activation of AMPK signaling was involved in the negative.modulation of YAP signaling pathway in these cells