Xu Li-Quan, Tan Shu-Bin, Huang Shan, Ding He-Yuan, Li Wen-Gang, Zhang Yi, Li Shi-Qi, Wang Tao
Department of Neurosurgery, Shanghai 5th People's Hospital, Shanghai Medical College, Fudan University, Shanghai, 200240, China.
Department of Endocrinology, Shanghai 5th People's Hospital, Shanghai Medical College, Fudan University, Shanghai, 200240, China.
Oncotarget. 2017 Apr 18;8(33):54227-54235. doi: 10.18632/oncotarget.17203. eCollection 2017 Aug 15.
The expression and potential biological functions of G protein-coupled receptor kinase 6 (GRK6) in human glioma are tested in this study. We show that protein and mRNA expression of GRK6 in human glioma tissues was significantly higher than that in the normal brain tissues. Further immunohistochemistry assay analyzing total 118 human glioma tissues showed that GRK6 over-expression was correlated with glioma pathologic grade and patients' Karnofsky performance status (KPS) score. At the molecular level, in the GRK6-low H4 glioma cells, forced over-expression of GRK6 promoted cell proliferation. Reversely, siRNA-mediated knockdown of GRK6 in the U251MG (GRK6-high) cells led to proliferation inhibition and cell cycle arrest. Intriguingly, GRK6 could also be an important temozolomide resistance factor. Temozolomide-induced cytotoxicity was prominent only in GRK6-low H4 glioma cells. On the other hand, knockdown of GRK6 by targeted siRNA sensitized U251MG cells (GRK6-high) to temozolomide. Thus, GRK6 over-expression in glioma is important for cell proliferation and temozolomide resistance.
本研究检测了G蛋白偶联受体激酶6（GRK6）在人类胶质瘤中的表达及潜在生物学功能。我们发现，GRK6在人类胶质瘤组织中的蛋白质和mRNA表达显著高于正常脑组织。进一步对总共118例人类胶质瘤组织进行免疫组织化学分析表明，GRK6的过表达与胶质瘤病理分级及患者的卡氏功能状态（KPS）评分相关。在分子水平上，在GRK6低表达的H4胶质瘤细胞中，GRK6的强制过表达促进细胞增殖。相反，在U251MG（GRK6高表达）细胞中，siRNA介导的GRK6敲低导致增殖抑制和细胞周期停滞。有趣的是，GRK6也可能是一个重要的替莫唑胺耐药因子。替莫唑胺诱导的细胞毒性仅在GRK6低表达的H4胶质瘤细胞中显著。另一方面，靶向siRNA敲低GRK6使U251MG细胞（GRK6高表达）对替莫唑胺敏感。因此，胶质瘤中GRK6的过表达对细胞增殖和替莫唑胺耐药性很重要。
