Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.
PLoS Genet. 2023 Feb 21;19(2):e1010640. doi: 10.1371/journal.pgen.1010640. eCollection 2023 Feb.
The molecular mechanism of tumor metastasis, especially how metastatic tumor cells colonize in a distant site, remains poorly understood. Here we reported that ARHGAP15, a Rho GTPase activating protein, enhanced gastric cancer (GC) metastatic colonization, which was quite different from its reported role as a tumor suppressor gene in other cancers. It was upregulated in metastatic lymph nodes and significantly associated with a poor prognosis. Ectopic expression of ARHGAP15 promoted metastatic colonization of gastric cancer cells in murine lungs and lymph nodes in vivo or protected cells from oxidative-related death in vitro. However, genetic downregulation of ARHGAP15 had the opposite effect. Mechanistically, ARHGAP15 inactivated RAC1 and then decreased intracellular accumulation of reactive oxygen species (ROS), thus enhancing the antioxidant capacity of colonizing tumor cells under oxidative stress. This phenotype could be phenocopied by inhibition of RAC1 or rescued by the introduction of constitutively active RAC1 into cells. Taken together, these findings suggested a novel role of ARHGAP15 in promoting gastric cancer metastasis by quenching ROS through inhibiting RAC1 and its potential value for prognosis estimation and targeted therapy.
肿瘤转移的分子机制，特别是转移性肿瘤细胞在远处定植的机制，仍知之甚少。在这里，我们报道了 ARHGAP15，一种 Rho GTPase 激活蛋白，增强了胃癌（GC）的转移定植，这与它在其他癌症中作为肿瘤抑制基因的作用有很大不同。它在转移性淋巴结中上调，并与预后不良显著相关。ARHGAP15 的异位表达促进了胃癌细胞在小鼠肺部和淋巴结中的转移定植，或在体外保护细胞免受氧化相关死亡。然而，ARHGAP15 的遗传下调则产生了相反的效果。从机制上讲，ARHGAP15 使 RAC1 失活，然后减少细胞内活性氧（ROS）的积累，从而增强了定植肿瘤细胞在氧化应激下的抗氧化能力。这种表型可以通过抑制 RAC1 来模拟，也可以通过向细胞中引入组成性激活的 RAC1 来挽救。总之，这些发现表明 ARHGAP15 通过抑制 RAC1 来清除 ROS，从而在促进胃癌转移方面发挥了新的作用，并具有用于预后评估和靶向治疗的潜在价值。
