ARHGAP15 promotes metastatic colonization in gastric cancer by suppressing RAC1-ROS pathway

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. Author summaryAlthough metastasis is an extremely insufficient process, it constitutes the major cause of gastric cancer related death. Up to present, little is known about the metastatic colonization, especially how the quite limited tumor cells survive in distant sites to develop metastatic lesions. Here, we reported a Rho GTPase activating protein ARHGAP15, which was identified as a leading upregulated gene in metastatic lymph nodes but previously reported as a tumor suppressor in other malignancies, promoted metastatic colonization of gastric cancer in vivo and protected cell from oxidative-related death in vitro. Further studies indicated that ARHGAP15 suppressed RAC1 and then decreased intracellular reactive oxygen species produced by NOX2, a downstream gene of RAC1, thus protecting colonizing tumor cells from oxidative stress. Our research contributed to a more comprehensive and detailed understanding of the dynamics of metastatic colonization and more importantly, demonstrated the pro-metastatic role of ARHGAP15 for the first time, providing novel insights into the role of this Rho GTPase activating protein.