TCF7L2 promotes tumor progression by regulating hypoxia-inducible factor 1 alpha through activating the PI3K/AKT signaling pathway in colorectal carcinoma

Hypoxia is a critical pathogenic factor in cancer development and metastasis. The pivotal role of hypoxia-inducible factor 1α (HIF-1α) in tumor progression under hypoxic conditions is well-documented. However, the specific mechanisms by which HIF-1α contributes to colorectal cancer (CRC) progression remain inadequately elucidated. In this study, we observed an upregulation of Transcription Factor 7-like 2 (TCF7L2) in CRC cells under hypoxic conditions. Meanwhile, hypoxia-induced overexpression of TCF7L2 plays a pivotal role in the proliferation, apoptosis, cell cycle arrest, migration, invasion, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) characteristics of colorectal cancer (CRC) cells in vitro. Additionally, our findings indicate that the inhibition of TCF7L2 results in a significant reduction of tumor growth in vivo. Mechanistically, hypoxia-induced up-regulation of TCF7L2 expression occurs in a HIF-1α-dependent manner. Chromatin immunoprecipitation (ChIP) assays demonstrated increased HIF-1α binding to the promoter sequence of TCF7L2 following hypoxic stimulation. Furthermore, our findings indicate that TCF7L2 plays an oncogenic role in colorectal cancer (CRC) by activating the PI3K/AKT signaling pathway. Additionally, we observed that elevated expression levels of both HIF-1α and TCF7L2 in CRC specimens are associated with aberrant clinicopathological features. Co-expression of TCF7L2 and HIF-1α predicts a poor prognosis in CRC patients. Targeting TCF7L2 is a promising approach to colorectal cancer therapy.