ARHGAP15 attenuates the Rac1 activity and ROS level to promote cell survival under oxidative stress and gastric cancer metastasis

Abstract

Gastric cancer (GC) is an aggressive malignant disease that continues to have a daunting impact on global health. GC is often diagnosed at an advanced stage with very poor outcome. Though lots of research has been undertaken in GC, the mechanisms behind the metastasis of GC are remaining poorly understood.

In this study, I aimed to investigate key regulators contributing to the GC metastasis process. To fulfill this aim, RNA sequencing was applied to compare gene expression profiles among the primary tumor, its adjacent non-tumor tissue and lymph node metastatic tumor tissue in 4 gastric cancers and 4 cardia cancers. After data analysis, ARHGAP15, a Rho GTPase activating protein, was identified to be significantly overexpressed in metastatic tumor tissue compared with both the non-tumor and primary tumor tissue. Analysis of data from The Cancer Genome Atlas (TCGA) and tissue microarray (TMA) showed that ARHGAP15 expression was higher in gastric cancer patients with lymph node metastasis than in patients without metastasis. In addition, upregulation of ARHGAP15 was significantly associated with poor outcomes of GC patients.

The in vivo experiments demonstrated that ARHGAP15 overexpression could promote lung metastatic colonization after tail vein injection and ARHGAP15 could also promote the early seeding of cancer cells in the lung. At the cell level, it was demonstrated that ARHGAP15 could inhibit the cell death induced by H2O2 and TRAIL and promote the single cell survival ability under stress. Further mechanism study showed that ARHGAP15 inhibited the Rac1 activity and then reduced the intracellular ROS production and promoted the tumor cell to achieve the antioxidative status. Moreover, the effect of ARHGAP15 on cell survival was demonstrated on regulating the intracellular ROS level.

These findings from this study suggest that the metastatic tumor cells take advantage of the ARHGAP15 overexpression to inhibit the oxidative stress induced cell death and promote the cell survival under stress. ARHGAP15 may be a promising target for gastric cancer metastasis.