He Xiao-Qin, Zhang Yue-Feng, Yu Jia-Jun, Gan Yuan-Yuan, Han Na-Na, Zhang Mei-Xia, Ge Wei, Deng Jun-Jian, Zheng Yong-Fa, Xu Xi-Ming
1 Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China.
2 Department of Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Tumour Biol. 2017 Mar;39(3):1010428317695971. doi: 10.1177/1010428317695971.
The aim of this study was to investigate the role of G-protein signaling modulator 2 in the carcinogenesis and progression of hepatocellular carcinoma. We previously showed that G-protein signaling modulator 2 was upregulated in hepatitis B virus-related hepatocellular carcinoma tissues through a hierarchical clustering analysis. With this study, we first assessed the expression pattern of G-protein signaling modulator 2 in hepatocellular carcinoma specimens and adjacent noncancerous tissues; clinical data were analyzed, along survival times, utilizing the Kaplan-Meier method. Moreover, the functions of G-protein signaling modulator 2 were examined using small-interfering RNAs in vitro. The results showed that G-protein signaling modulator 2 was clearly overexpressed in hepatocellular carcinoma tissues and cell lines and that the G-protein signaling modulator 2 expression level was related to tumor size and hepatitis B virus infection. Furthermore, G-protein signaling modulator 2 knockdown studies suggested that G-protein signaling modulator 2 accelerates cell growth, cell cycle, migration, and invasion and inhibits apoptosis, acting as an oncogene in hepatocellular carcinoma. Western blotting indicated that silencing of G-protein signaling modulator 2 in HepG2 and SMMC-7721 cells increased the expression levels of Bax, caspase-3, and E-cadherin, while notably suppressing the cyclin-dependent kinase 4, cyclin-dependent kinase 6, CyclinD1, Snail1, Vimentin, and matrix metallopeptidase 9 expression levels, compared with that in the control groups. In addition, we found that G-protein signaling modulator 2 can affect the expression of key proteins involved in protein kinase B activation. In conclusion, high expression of G-protein signaling modulator 2 was involved in the pathological processes of hepatocellular carcinoma through activation of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, which may provide an attractive potential diagnostic biomarker and therapeutic target for treatment of hepatocellular carcinoma.
本研究旨在探讨G蛋白信号调节因子2在肝细胞癌发生发展中的作用。我们之前通过分层聚类分析表明，G蛋白信号调节因子2在乙型肝炎病毒相关肝细胞癌组织中上调。在本研究中，我们首先评估了G蛋白信号调节因子2在肝细胞癌标本和癌旁非癌组织中的表达模式；利用Kaplan-Meier方法分析临床数据以及生存时间。此外，在体外使用小干扰RNA检测了G蛋白信号调节因子2的功能。结果显示，G蛋白信号调节因子2在肝细胞癌组织和细胞系中明显过表达，且G蛋白信号调节因子2的表达水平与肿瘤大小和乙型肝炎病毒感染有关。此外，G蛋白信号调节因子2敲低研究表明，G蛋白信号调节因子2促进细胞生长、细胞周期、迁移和侵袭，并抑制细胞凋亡，在肝细胞癌中作为癌基因发挥作用。蛋白质印迹法表明，与对照组相比，沉默HepG2和SMMC-7721细胞中的G蛋白信号调节因子2可增加Bax、半胱天冬酶-3和E-钙黏蛋白的表达水平，同时显著抑制细胞周期蛋白依赖性激酶4、细胞周期蛋白依赖性激酶6、细胞周期蛋白D1、Snail1、波形蛋白和基质金属肽酶9的表达水平。此外，我们发现G蛋白信号调节因子2可影响参与蛋白激酶B激活的关键蛋白的表达。总之，G蛋白信号调节因子2的高表达通过激活磷脂酰肌醇3-激酶/蛋白激酶B信号通路参与肝细胞癌的病理过程，这可能为肝细胞癌的治疗提供一个有吸引力的潜在诊断生物标志物和治疗靶点。
