RBM3-associated germline variants and their functional role in gastric cancer susceptibility and progression

Background: Gastric cancer (GC) is the fifth most commonly diagnosed malignancy and the fourth leading cause of cancer-related mortality worldwide. RNA-binding motif protein 3 (RBM3) has been associated as a prognostic marker in several cancers; however, its genetic contribution and functional role in gastric cancer remain unclear. Methods: Genome-wide association study (GWAS) data was integrated with experimental validation to investigate the role of RBM3 in GC. RBM3-associated expression quantitative trait loci (eQTLs) were identified from a GWAS of 3,301 individuals and evaluated for their association with GC risk using a large-scale GWAS comprising 456,348 individuals. Colocalization analysis was performed using stomach tissue eQTL data. RBM3 expression was assessed in 60 paired GC and adjacent normal tissues and in multiple GC cell lines. Functional effects of RBM3 modulation were examined through proliferation, colony formation, migration, invasion, and xenograft assays. Results: , RBM3 overexpression suppressed xenograft tumor growth, reduced Ki67-positive proliferation, and enhanced apoptotic activity. Conclusion: Our findings demonstrate that RBM3 acts as a genetically supported tumor suppressor in gastric cancer. RBM3-associated germline variants contribute to GC susceptibility, and RBM3 downregulation promotes aggressive tumor behavior. RBM3 therefore represents a promising biomarker and potential therapeutic target in gastric cancer.