Abstract
Helicobacter pylori (H. pylori) plays an important role in the malignant transformation of the gastric mucosa from chronic inflammation to cancer. However, the mechanisms underlying the epigenetic regulation of gastric carcinogenesis mediated by H. pylori remain unclear. Here, we uncover that H. pylori inhibits METTL14 by upregulating ATF3. METTL14 inhibits gastric cancer (GC) cell proliferation and metastasis in vitro and in vivo. Downregulation of METTL14 inhibits Vesicle-associated membrane protein-3 (VAMP3) by reducing the m(6)A modification level of VAMP3 mRNA and the stability of IGF2BP2-dependent mRNA. H. pylori also accelerates the malignant progression of GC by regulating VAMP3/LC3C-mediated c-Met recycling. Moreover, the expression of METTL14 and VAMP3 in Hp+ chronic gastritis tissues is much lower than that in Hp- chronic gastritis tissues. METTL14 and VAMP3 expression levels are downregulated notably in cancerous tissues of patients with GC. Therefore, our results show a novel METTL14-VAMP3-LC3C-c-Met signalling axis in the GC development mediated by H. pylori infection, which reveals a novel m(6)A epigenetic modification mechanism for GC and provides potential prognostic biomarkers for GC progression.