HIF-1α stimulates the progression of oesophageal squamous cell carcinoma by activating the Wnt/β-catenin signalling pathway

Background This study aimed to clarify the significance of the crosstalk between hypoxia-inducible factor-1 alpha (HIF-1 alpha) and the Wnt/beta-catenin pathway in oesophageal squamous cell carcinoma (ESCC). Methods The oncogenic role of HIF-1 alpha in ESCC was investigated using in vitro and in vivo assays. The clinicopathological significance of HIF-1 alpha, beta-catenin and TCF4/TCF7L2 in ESCC were evaluated using quantitative real-time PCR and immunohistochemistry. Results The expression level of HIF-1 alpha, beta-catenin, and TCF4/TCF7L2 in T.Tn and TE1 cell lines were elevated under hypoxia in vitro. HIF-1 alpha knockdown suppressed proliferation, migration/invasion and epithelial-mesenchymal transition (EMT) progression, induced G0/G1 cell cycle arrest, promoted apoptosis and inhibited 5-fluorouracil chemoresistance in vitro. In vivo assays showed that HIF-1 alpha is essential in maintaining tumour growth, angiogenesis, and 5-fluorouracil chemoresistance. Mechanically, we identified the complex between HIF-1 alpha and beta-catenin, HIF-1 alpha can directly bind to the promoter region of TCF4/TCF7L2. The mRNA level of HIF-1 alpha, beta-catenin and TCF4/TCF7L2 were increased in ESCC tumour tissues compared to the corresponding non-tumour tissues. High levels of HIF-1 alpha and TCF4/TCF7L2 expression were correlated with aggressive phenotypes and poor prognosis in ESCC patients. Conclusions HIF-1 alpha serves as an oncogenic transcriptional factor in ESCC, probably by directly targeting TCF4/TCF7L2 and activating the Wnt/beta-catenin pathway.