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: Several independent variants within the RBM3 locus showed a consistent protective association with GC risk and were linked to RBM3 expression regulation. RBM3 expression was significantly reduced in GC tissues compared with adjacent normal tissues (P < 0.001). Low RBM3 expression correlated with advanced tumor stage (III-IV), lymph node and distant metastasis, and larger tumor size. Functionally, RBM3 overexpression inhibited GC cell proliferation, clonogenicity, migration, and invasion in vitro. In vivo, 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.