HIF1-driven TDP-43 stabilizes TRIP6 mRNA to drive angiogenesis and colorectal cancer progression under hypoxia

Hypoxia is a key feature of the tumor microenvironment in colorectal cancer (CRC), but the mechanisms linking hypoxia to metastasis remain incompletely understood. To investigate this, bioinformatics analysis of The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) datasets assessed TAR DNA-binding protein 43 (TDP-43) expression and its correlation with hypoxia-inducible factor-1α (HIF1A). In vitro and in vivo functional assays, including Cell Counting Kit-8 (CCK-8), Transwell, chicken chorioallantoic membrane (CAM), and xenograft, were conducted to evaluate proliferation, migration, invasion, and angiogenesis. Mechanistic studies, including chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), luciferase reporter, and actinomycin D assay, were conducted to elucidate HIF1-mediated transcriptional regulation of TARDBP and TDP-43-dependent stabilization of thyroid receptor-interacting protein 6 (TRIP6) mRNA. As a result, TDP-43 was upregulated in CRC tissues and correlated with HIF1A expression. Hypoxia induced TDP-43 expression through HIF1-dependent transcriptional activation via direct binding to hypoxia-response element (HRE) 3 site in the TARDBP promoter. TARDBP knockdown suppressed hypoxia-induced proliferation, migration, invasion, and vascular endothelial growth factor (VEGF) secretion, which were rescued by HIF1A overexpression. RIP-qPCR revealed TDP-43 binding to TRIP6 mRNA via its RNA recognition motifs (RRM domains), stabilizing TRIP6 transcripts and promoting its expression. TRIP6 reconstitution reversed the anti-tumor effects of TARDBP silencing. In vivo, TARDBP depletion inhibited tumor growth and downregulated metastasis-related factors in xenograft models. In conclusion, the HIF1-TARDBP-TRIP6 axis promotes CRC malignancy under hypoxia by integrating transcriptional activation and post-transcriptional mRNA stabilization, offering potential therapeutic targets for advanced CRC.