GPR176 enhances the epithelial-mesenchymal transition in gastric cancer cells by activating the PI3K/AKT/mTOR signaling pathway

Gastric cancer is characterized by a high incidence and unfavorable prognosis. The exploration of novel molecular markers and a deeper understanding of their mechanisms of action hold the potential to offer fresh insights into gastric cancer treatment. Leveraging the TCGA-STAD and GSE66254 datasets, this study conducted an analysis on the relationship between GPR176 and clinical pathological features. Furthermore, it was validated in patients from The First Affiliated Hospital of Guangxi Medical University. Cell migration and invasion capabilities were evaluated through Transwell and scratch assays. Western blot was performed to detect the impact of GPR176 on PI3K/AKT/mTOR signaling pathway. Nude mouse tumorigenesis experiments were conducted to validate the impact of GPR176 on tumor growth in vivo . GPR176 exhibited higher expression levels in gastric cancer tissues, and was associated with a poor prognosis in patients with gastric cancer. Significant downregulation of GPR176 suppressed the invasive and migratory capabilities of gastric cancer cells, concomitant with the inhibition of the PI3K and EMT signaling pathways. However, the phenotypic changes induced by GPR176 downregulation and its inhibitory effects could be reversed by the overexpression of PIP5K1A. Nude mouse tumorigenesis experiments validated the findings from cell experiments, demonstrating that GPR176 downregulation suppressed tumor growth, while GPR176 overexpression promoted tumor growth. Similarly, after GPR176 downregulation, the EMT and PI3K/AKT/mTOR signaling pathways in tumor cells were significantly inhibited, whereas GPR176 upregulation led to their substantial activation. In conclusion, GPR176 emerged as a newly identified prognostic marker in this study. GPR176 may promote the EMT of gastric cancer cells by activating the PI3K/AKT/mTOR signaling pathway.