Fragile X mental retardation 1 gene FMR1 promotes proliferation, migration, and invasion of gastric cancer cells via c-MYC.

BACKGROUND: Gastric cancer is a highly aggressive malignancy with poor prognosis and low survival rates. The Fragile X Mental Retardation 1 (FMR1) gene has been implicated in the development and progression of various tumors, but its role in gastric cancer remains unclear. METHODS: We performed pan-cancer expression analysis of FMR1 using the TIMER2.0 platform, and evaluated its differential expression in gastric cancer versus normal gastric tissues in the TCGA cohort. FMR1 expression was validated by qRT-PCR, Western blotting, and immunohistochemistry. Using R software and clinical samples to evaluate the association between FMR1 expression levels and clinicopathological factors in gastric cancer patients, and to analyze patient survival curves. The relationship between FMR1 expression and tumor immune infiltration was analyzed via the TISIDB database, and after co-culture, cytokine secretion by CD4⁺ T cells was assessed using ELISA following FMR1 knockdown in tumor cells. Functional enrichment analyses of FMR1 and its interacting genes were performed. Single-cell transcriptomics was used to extend the interpretation of intratumoral lineages and states. Malignant epithelial populations were identified using inferCNV, and these cells were subsequently stratified by FMR1 expression for GSVA. We measured FMR1 expression in control and FMR1 knockdown gastric cancer cells, performed proliferation, migration, and invasion assays to investigate the biological effects of FMR1 in gastric cancer. Mechanistic insights were further explored through co-immunoprecipitation, cycloheximide chase, proteasome inhibition, and rescue assays. RESULTS: FMR1 was significantly overexpressed in gastric cancer tissues compared to normal gastric mucosa, with high expression levels associated with poor prognosis. The differential expression of FMR1 in gastric cancer was strongly associated with the activity of multiple immune cell types within the tumor microenvironment. Functional assays further demonstrated that FMR1 knockdown suppressed cytokine secretion by CD4⁺ T cells. The expression level of FMR1 in malignant epithelial cells is higher than that in the non-malignant group, and the high-expression group of FMR1 in malignant cells shows a consistent increase in the Hallmark gene sets directly related to stem cell like phenotype, chemotherapy resistance, and immune evasion. Knockdown of FMR1 suppressed gastric cancer cell proliferation, migration, and invasion, while mechanistic studies indicated that FMR1 positively regulates c-MYC expression to drive these phenotypes. And we found that FMR1 interacted with c-MYC at the protein level and stabilized c-MYC by suppressing its proteasomal degradation. CONCLUSION: Our findings demonstrate that FMR1 promotes gastric cancer cell proliferation, migration, and invasion through c-MYC signaling, suggesting that FMR1 may serve as a potential prognostic biomarker and therapeutic target for gastric cancer.