SOD2 promotes gastric tumorigenesis mediated by Helicobacter pylori and enhances resistance to 5-fluorouracil in gastric cancer

Abstract

Abstract Background: Helicobacter pylori (H. pylori) infection is the most common risk factor for gastric cancer (GC). The effect of the antioxidase manganese superoxide dismutase (SOD2 or MnSOD) in gastric tumorigenesis remains unclear. Methods: We explored the molecular and mechanical links between H. pylori, inflammation, and SOD2 in GC. RNA sequencing was conducted to identify the differentially expressed mRNAs between H. pylori-infected and uninfected cells. The putative role of SOD2 in gastric tumorigenesis in response to H. pylori infection was investigated in vitro and in vivo. Results: SOD2 is upregulated in GC. GC patients with high SOD2 expression clearly showed worse overall survival. H. pylori infection promoted SOD2 expression by activating the NF-κB signaling pathway. Knockdown of SOD2 led to increased levels of reactive oxygen species and oxidative stress in response to H. pylori infection. Meanwhile, the NF-κB binding site in the SOD2promoter region was evaluated through luciferase reporter and chromatin immunoprecipitation assays. SOD2 acted as an inhibitor of ferroptosis in GC cells, and SOD2 inhibition significantly sensitized GC cells to 5-fluorouracil treatment. Conclusions: Our results suggest that activation of the NF-κB pathway in GC cells infected with H. pylori leads to the upregulation of SOD2. Considering the prosurvival oncogenic features of SOD2 overexpression, our study further supports a novel relationship between infection, inflammation, and gastric carcinogenesis. Our results indicate that SOD2 may be a promising therapeutic candidate for GC.