RREB1-driven FMR1 upregulation promotes colorectal cancer angiogenesis via VEGFA-mediated MAPK/PI3K signaling activation.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, and angiogenesis is a critical driver of tumor growth and metastasis. In this study, we found that FMR1, an RNA-binding protein, was markedly upregulated in CRC tissues and was positively associated with microvessel density (MVD), CD34 expression, and VEGFA levels. Functional experiments, including HUVEC tube formation and chick chorioallantoic membrane (CAM) assays, showed that FMR1 overexpression promoted angiogenesis, whereas FMR1 knockdown suppressed this process. Mechanistically, FMR1 enhanced VEGFA expression and secretion, thereby activating MAPK and PI3K signaling pathways in endothelial cells and promoting their proliferation and tube formation. Notably, VEGFA silencing attenuated the pro-angiogenic effects induced by FMR1. In addition, we identified RREB1 as an upstream transcriptional activator of FMR1. ChIP-qPCR and luciferase reporter assays demonstrated that RREB1 directly binds to the FMR1 promoter, and RREB1 expression was positively correlated with FMR1 levels in CRC tissues. Collectively, these findings reveal a previously unrecognized RREB1-FMR1-VEGFA signaling axis that promotes angiogenesis in CRC, highlighting its potential as a prognostic biomarker and therapeutic target.