State Key Laboratory of Oncology in South PR China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China.
Department of Gastric Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, PR China.
J Pathol. 2019 Sep;249(1):126-136. doi: 10.1002/path.5287. Epub 2019 Jun 27.
RhoA has been identified as having a gain-of-function mutation in approximately 20% of diffuse gastric cancer patients. However, the carcinogenic role of RhoA mutations in gastric cancer (GC) is unclear. In the present study, we report that RhoA directly interacts with c-Met and can be phosphorylated by c-Met at Y42 before subsequent K48-linked polyubiquitination and proteasome-mediated protein degradation. Y42C-mutated RhoA exhibits higher protein levels and promotes the proliferation and motility of GC cells. Interestingly, a c-Met inhibitor significantly repressed the growth of GC cells transfected with WT RhoA but not RhoA mutated at Y42 in vivo and in vitro. Analyses of human GC tissues showed that the combined levels of p-c-Met and p-RhoA are a better predictor for prognosis than either factor alone. Taken together, our findings unravel the mechanism by which the RhoA Y42 mutant is linked to poor prognosis in GC. Moreover, this study helps to identify a strategy for patient stratification and optimization of targeted c-Met therapy. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
RhoA 被鉴定在大约 20%的弥漫性胃癌患者中具有功能获得性突变。然而，RhoA 突变在胃癌（GC）中的致癌作用尚不清楚。在本研究中，我们报告 RhoA 可直接与 c-Met 相互作用，并可被 c-Met 在 Y42 处磷酸化，随后发生 K48 连接的多泛素化和蛋白酶体介导的蛋白降解。Y42C 突变型 RhoA 表现出更高的蛋白水平，并促进 GC 细胞的增殖和迁移。有趣的是，c-Met 抑制剂可显著抑制转染 WT RhoA 的 GC 细胞的生长，但在体内和体外对 Y42 突变型 RhoA 没有作用。对人 GC 组织的分析表明，p-c-Met 和 p-RhoA 的联合水平比任一因子单独预测预后更好。总之，我们的研究结果揭示了 RhoA Y42 突变与 GC 预后不良相关的机制。此外，这项研究有助于确定一种患者分层策略，并优化针对 c-Met 的治疗。
