648. HYPOXIA-INDUCIBLE FACTOR 1α (HIF-1α) STIMULATES THE PROGRESSION OF ESOPHAGEAL SQUAMOUS CELL CARCINOMA BY ACTIVATING THE WNT/β-CATENIN SIGNALLING PATHWAY

Abstract

Hypoxia inducible factor -1α (HIF-1α) and Wnt/β-catenin signal pathway has been reported to be involved in tumor progression in various types of cancers. However, the molecular mechanism by which HIF-1α regulate malignant features in esophageal squamous cell carcninoma (ESCC) are still poorly understood. This study aimed to clarify the significance of the crosstalk between HIF-1α and the Wnt/β-catenin pathway in ESCC. The oncogenic role of HIF-1α in ESCC was investigated using in vitro and in vivo assays. The clinicopathological significance of HIF-1α, β-catenin and TCF4/TCF7L2 in ESCC were evaluated using quantitative real-time PCR and immunohistochemistry. Then we performed qRT-PCR, western blotting, Cell Counting-8 assay, trans-well assay, flow cytometry, immunofluorescence, Co-IP and ChIP assays, chemo resistance test in vitro, tumor xenograft model in vivo. The expression level of HIF-1α, β-catenin, and TCF4/TCF7L2 in ESCC cell lines were elevated under hypoxia in vitro. HIF-1α knockdown suppressed proliferation, igration/invasion and EMT progression, induced G0/G1 cell cycle arrest, promoted apoptosis and inhibited 5-fluorouracil chemoresistance in vitro. In vivo assays showed that HIF-1α is essential in maintaining tumour growth and 5-fluorouracil chemoresistance. Mechanically, we identified the complex between HIF-1α and β-catenin, HIF-1α can directly bind to the promoter region of TCF4/TCF7L2. The mRNA level of HIF-1α, β-catenin and TCF4/TCF7L2 were increased in ESCC tumor tissues. High levels of HIF-1α and TCF4/TCF7L2 were correlated with poor prognosis in ESCC. HIF-1α serves as an oncogenic transcriptional factor in ESCC, probably by directly targeting TCF4/TCF7L2 and activating the Wnt/β-catenin pathway. Our study clarifies the critical role of HIF-1α in ESCC progression.