HER2 Regulates Autophagy and Promotes Migration in Gastric Cancer Cells Through the CGAS-STING Pathway

In gastric cancer, the relationship between human epidermal growth factor receptor 2 (HER2), the cyclic GMP-AMP synthase-stimulator of the interferon genes (cGAS-STING) pathway, and autophagy remains unclear. This study examines whether HER2 regulates autophagy in gastric cancer cells via the cGAS-STING signaling pathway, influencing key processes such as cell proliferation and migration. Understanding this relationship could uncover new molecular targets for diagnosis and treatment. Through lentiviral transfection, cell counting kit-8 assays, colony formation, transwell migration, scratch assays, and siRNA, we found that HER2 overexpression suppresses the cGAS-STING pathway, inhibits autophagy, and enhances the migratory ability of gastric cancer cells. In contrast, HER2 knockdown activates the cGAS-STING pathway, promotes autophagy, and reduces cell migration. We further observed that the inhibition of autophagy using chloroquine (CQ) increases the migration ability of HER2-overexpressing cells. Moreover, interfering with STING expression reversed the migration defects caused by HER2 knockdown, underscoring the critical role of the cGAS-STING pathway in HER2-regulated cell migration. We also revealed that high STING expression in gastric cancer is significantly associated with poor prognosis. STING expression was identified as an independent prognostic factor for survival (hazard ratio, 1.942; 95% confidence interval, 1.06-3.54; P  = 0.031). These results highlight the importance of HER2-driven regulation of autophagy through the cGAS-STING pathway in gastric cancer progression and its potential as a therapeutic target.