The association between overactivation of renin-angiotensin system and long-term survival in patients with gastric cancer

Background The renin-angiotensin system (RAS) plays a crucial role in regulating the molecular mechanisms of chronic stress and is often linked to adverse effects in various cancers. In this study, we aimed to investigate the association between the overexpression of key RAS regulatory genes and overall survival in gastric cancer patients. Methods The association between the overexpression of key RAS regulatory genes and long-term outcomes in gastric cancer patients was analyzed using the web-based gene survival tool, Kaplan-Meier Plotter (KM Plotter). The 10-year overall survival rates were calculated for study cohorts stratified based on the best expression levels of key RAS regulatory genes, including angiotensinogen (AGT) (202834_at), renin (REN) (206367_at), angiotensin-converting enzyme-1 (ACE1) (209749_s_at), ACE2 (219962_at), angiotensin receptor-1 (AGTR1) (208016_s_at), angiotensin receptor-2 (AGTR2) (222321_at), and peroxisome proliferator-activated receptor gamma (PPARγ) (208510_s_at). Results A total of 875 gastric cancer patients were selected from KM plotter to assess association between key regulatory genes overexpression and 10-year overall survival. The overexpression of key regulator genes including AGT (HR=1.55, 95% CI 1.31-1.84), REN (HR=1.33, 95% CI 1.12-1.58), ACE1 (HR=1.85, 95% CI 1.49-2.31), AGTR1 (HR=2.04, 95% CI 1.65-2.51) and AGTR2 (HR=1.72, 95% CI 1.44-2.05) were associated with increased risk of all-cause death except ACE2 (HR=0.77, 95% CI 0.65-0.92), which attenuates harmful effects of RAS by catalyzing the hydrolysis of angiotensin II. The 10-year overall survival was significantly lower for the cohorts with overexpression of AGT, REN, ACE1 (Figure 1A-C), AGTR1 and AGTR2 (Figure 1E and 1F), while it was significantly higher for cohorts with overexpression of ACE2 (Figure 1D). The PPARγ mediated inhibitory pathway (Figure 1G) could attenuate harmful effects of RAS. The overexpression of PPARγ was significantly associated with reduced risk of death (HR=0.70, 95% CI 0.58-0.85) and associated with better overall survival (Figure 1H). Conclusion The overexpression of key regulator genes of RAS are significantly associated with increased risk of death and lower overall survival in gastric cancer patients. While upregulation of PPARγ mediated inhibitory pathways of RAS significantly increases overall survival rate in gastric cancer patients.