Spermine oxidase promotes Helicobacter pylori-mediated gastric carcinogenesis through acrolein production

Helicobacter pylori is the primary cause of gastric cancer and there is a need to discover new molecular targets for therapeutic intervention in H. pylori disease progression. We have previously shown that spermine oxidase (SMOX), the enzyme that catabolizes the back-conversion of the polyamine spermine to spermidine, is upregulated during infection and is associated with increased cancer risk in humans. We sought to determine the direct role of SMOX in gastric carcinogenesis during H. pylori infection. In this study, we demonstrate that transgenic FVB/N insulin-gastrin (INS-GAS) mice that develop gastric carcinoma with H. pylori infection were protected from cancer development with Smox deletion. RNA sequencing revealed that genes associated with the immune system and cancer were downregulated in the infected Smox–/– mice. Furthermore, there was a decrease in cell proliferation and DNA damage in infected Smox–/– animals. There was significant generation of adducts of the highly reactive electrophile acrolein, a byproduct of SMOX activity, in tissues from H. pylori-infected WT mice and humans. Genetic deletion of Smox or chemical inhibition of SMOX in murine organoids and human gastric epithelial cells and organoids, respectively, significantly reduced generation of acrolein induced by H. pylori. Furthermore, acrolein induced DNA damage in gastric epithelial cells, which was ablated with the electrophile scavenger 2-hydroxybenzylamine (2-HOBA). Infected 2-HOBA treated INS-GAS WT mice with reduced gastric carcinoma had attenuated gastric acrolein adduct formation. These findings implicate SMOX and acrolein in H. pylori-induced carcinogenesis in gastric epithelial cells, thus indicating potential therapeutic targets. RNA sequencing by Illumina NovaSeq6000 was performed on gastric tissues of WT and Smox-/- mice infected or not with H. pylori PMSS1 for 8 weeks to determine the role of SMOX in H. pylori pathogenesis RNA was extracted from the gastric tissue from 4-5 mice per genotype either uninfected or infected