Helicobacter pylori infection promotes gastric carcinogenesis by inducing macrophage M2 polarization through the miR-146a-5p/TRAF6 signaling pathway

Background: Helicobacter pylori (Hp) Infection significantly elevates the risk of gastric Cancer formation. However, the molecular mechanisms by which it regulates macrophage polarization and promotes gastric Cancer progression have not been fully elucidated The present study aimed to investigate whether Hp Infection induces macrophage polarization toward M2 type through the miR-146a-5p/TRAF6 signaling pathway and regulates gastric Cancer cell function, which in turn promotes gastric Cancer development. The in vitro experimental study first infected macrophages with a differing multiplicity of Infection (MOI) of Hp. Flow cytometry detected the polarization direction and the dual luciferase assay detected the connection between miR-146a-5p and TRAF6. Subsequently, Hp-infected macrophages were co-cultured with gastric Cancer cells to detect the proliferation, migration and apoptotic ability of gastric Cancer cells. Finally, miR-146a-5p or miR-146a-5p and TRAF6 were overexpressed in macrophages to explore the effect of the miR-146a-5p/TRAF6 signaling axis on macrophage polarization and gastric Cancer cell function. For in vivo experiments, differently treated macrophages were treated with gastric Cancer cells and subsequently mixed and inoculated in nude mice to detect tumorigenicity in nude mice.

Results: Hp induces macrophage polarization toward M2 and inhibits its polarization toward M1, and miR-146a-5p targets the downstream gene TRAF6. Hp-infected macrophages stimulate the multiplication and movement of gastric Cancer cells and inhibit their Apoptosis. When the mechanism was explored, inhibition of miR-146a-5p or overexpression of TRAF6 inhibited macrophage polarization in the M2 direction, and M2-polarized macrophages inhibited the multiplication and movement of MFC and promoted their Apoptosis. For in vivo experiments, Hp and miR-146a-5p promote tumor formation, promote polarization of tumor macrophages toward M2 and inhibit tumor cell Apoptosis. These effects were partially counteracted by TRAF6.

Conclusion: Hp Infection induces macrophage polarization toward M2 type, inhibits its polarization toward M1 and regulates gastric Cancer cell function through the miR-146a-5p/TRAF6 signaling pathway, which in turn propels the development of gastric carcinoma. © 2026 Society of Chemical Industry.

Helicobacter pylori; gastric cancer; gastric cancer cells; macrophages; miR‐146a‐5p/TRAF6 signaling axis.