Wang Yizhuo, Xiao Huijie, Wu Haitao, Yao Cheng, He Hua, Wang Chang, Li Wei
Cancer Center, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
Department of Gastrointestinal Colorectal and Anal Surgery, China Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China.
Oncol Rep. 2017 Apr;37(4):1998-2006. doi: 10.3892/or.2017.5500. Epub 2017 Mar 13.
Genetic alterations in G protein subunit α q (GNAQ) have been reported in numerous types of human cancer. However, the role of GNAQ in human gastric cancer (GC) has not been explored. In the present study, we found that GNAQ was highly expressed in GC patient samples and GNAQ expression was related to patient age, GC differentiation status and adjuvant therapy, as determined by immunohistochemical assay. Lentivirus delivery of short hairpin RNA (shRNA) targeting GNAQ was used to explore the function of GNAQ in GC cells. Silencing of GNAQ markedly suppressed proliferation and colony formation in GC cells, and arrested the cell cycle at the S phase. Mechanistic analysis revealed that knockdown of GNAQ significantly increased the expression of p53 and p21, and decreased cyclin A and p-CDK2 protein expression. Moreover, the phosphorylation of ERK and MEK was also decreased after knockdown of GNAQ as determined by western blotting assay. Overall, our results suggest that GNAQ plays a critical role in regulating GC cell growth and survival via canonical oncogenic signaling pathways including MAPK and p53, and therefore serves as a promising new therapeutic target in GC.
在多种人类癌症中均已报道G蛋白亚基αq（GNAQ）存在基因改变。然而，GNAQ在人类胃癌（GC）中的作用尚未得到探索。在本研究中，我们发现GNAQ在GC患者样本中高表达，并且通过免疫组织化学分析确定，GNAQ表达与患者年龄、GC分化状态及辅助治疗相关。利用慢病毒递送靶向GNAQ的短发夹RNA（shRNA）来探究GNAQ在GC细胞中的功能。沉默GNAQ可显著抑制GC细胞的增殖和集落形成，并使细胞周期停滞于S期。机制分析显示，敲低GNAQ可显著增加p53和p21的表达，并降低细胞周期蛋白A和p-CDK2蛋白的表达。此外，通过蛋白质印迹分析确定，敲低GNAQ后ERK和MEK的磷酸化水平也降低。总体而言，我们的结果表明，GNAQ通过包括MAPK和p53在内的经典致癌信号通路在调节GC细胞生长和存活中起关键作用，因此可作为GC中有前景的新治疗靶点。
