YTHDF3 Promoted Gastric Cancer Progression by Facilitating m6A-Dependent Degradation of APC mRNA.

BACKGROUND: Stomach adenocarcinoma (STAD) is a highly prevalent malignancy. YTH domain family protein 3 (YTHDF3), an m6A reader, correlates with worse survival outcomes in STAD. The aim was to study the impact of YTHDF3 on STAD cells and its underlying regulatory mechanisms. METHODS: Epidemiologically, the GEPIA and Kaplan-Meier Plotter databases were used to examine YTHDF3 expression in STAD and to assess its association with prognosis, with poor prognosis defined by overall survival (OS). Clinical parameters were also analyzed to validate the prognostic value of YTHDF3. Experimentally, STAD patients were selected as the study objects. Immunofluorescence was used to confirm YTHDF3 expression in STAD tissues. In vitro assays examined YTHDF3/Adenomatous polyposis coli (APC) regulation of Wnt signaling. RESULTS: Epidemiologically, YTHDF3 elevation in STAD (p < 0.05) predicted poorer OS (hazard ratio [HR] = 1.46, 95% confidence interval [95% CI]: 1.17-1.81, p = 0.00066). High YTHDF3 expression was also significantly associated with advanced T stage (p = 0.0069), N stage (p = 0.0088), and positive distant metastasis (p = 0.0076). Experimentally, elevated YTHDF3 expression was observed in STAD tissues and cells (all p < 0.001). Silencing YTHDF3 suppresses AGS malignancy and promotes apoptosis. Conversely, YTHDF3 overexpression aggravated the malignant phenotype of STAD (all p < 0.001). Mechanistically, silencing YTHDF3 promoted APC expression (p < 0.001) in an m6A-dependent manner. Rescue experiments proved silencing APC reversed YTHDF3-knockdown-mediated repression of Wnt/β-catenin signaling and AGS cell malignancy (all p < 0.001). CONCLUSION: YTHDF3 promoted STAD progression by regulating APC mRNA degradation.