BACKGROUND: Gastric signet ring cell carcinoma (GSRCC) is a highly lethal malignancy. Serpin family E member 2 (SERPINE2) is a pro-tumorigenic factor in cancer. Here, we sought to define the role of SERPINE2 in the pathogenesis of GSRCC. METHODS: Messenger RNA (mRNA) expression was analyzed by quantitative polymerase chain reaction (PCR). Protein expression was tested by immunohistochemistry (IHC) and immunoblot assays. Proliferation was assessed by 5-ethynyl-2'-deoxyuridine (EdU) assay, and invasion and migration were detected by transwell assay. Tube formation assay was used to test the influence on angiogenesis. Cell apoptosis and M2 macrophage polarization were evaluated by flow cytometry. The methyltransferase-like 3 (METTL3)-SERPINE2 relationship was analyzed by RNA immunoprecipitation (RIP), luciferase, and mRNA stabilization assays. Xenograft experiments were used for assessment of METTL3's influence on tumorigenicity of GSRCC cells. RESULTS: SERPINE2 and METTL3 levels were upregulated in human GSRCC. Functionally, SERPINE2 depletion enhanced apoptosis of GSRCC cells and diminished their proliferative, migratory and invasive capacities CONCLUSIONS: Our study defines the significant roles of the METTL3/SERPINE2 axis as an epigenetic mechanism in GSRCC progression. Our work may have diagnostic and/or therapeutic applications in GSRCC.