ENOX1 promotes gastric cancer progression via Snail2-mediated epithelial-mesenchymal transition and M2-type tumour-associated macrophages polarisation.

Remodelling of the tumour microenvironment drives gastric cancer progression; however, the mechanism by which ecto-nicotinamide adenine dinucleotide oxidase 1 (ENOX1) regulates this process remains unknown. In the present study, we investigated the oncogenic functions of ENOX1 in gastric cancer. Analysis of public datasets and clinical samples revealed that ENOX1 was significantly overexpressed in gastric cancer tissues and correlated with poor prognosis. In vitro functional assays demonstrated that ENOX1 knockout suppressed the proliferation, migration, invasion, and clonogenicity of gastric cancer cells. Mechanistically, RNA sequencing and subsequent verification revealed that ENOX1 upregulates Snail2 expression and promotes epithelial-mesenchymal transition (EMT). Furthermore, ENOX1 expression in gastric cancer cells promotes the polarisation of co-cultured macrophages towards immunosuppressive M2-type tumour-associated macrophages (TAMs), as evidenced by the increased expression of CD206 and CD163. Rescue experiments indicated that Snail2 overexpression reverses the inhibitory effects of ENOX1 knockout on EMT and M2-type TAM polarisation. In an orthotopic mouse model, ENOX1 knockdown potently suppressed AKT/MYC-driven gastric tumourigenesis, reversed the EMT phenotype, and reduced M2-type TAM infiltration into tumour tissues. Collectively, our findings reveal that ENOX1 may promote gastric cancer progression via Snail2-mediated EMT and M2-type TAM polarisation, suggesting that ENOX1 is a potential therapeutic target.