Wnt/β-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1α signaling

Epithelialmesenchymal transition (EMT) is a critical process for tumor invasion and metastasis. Hypoxia may induce EMT, and upregulated -catenin expression has been found in various tumors. In this study, we investigate the role of -catenin in hypoxia-induced EMT in hepatocellular carcinoma (HCC). Induction of EMT in HCC cell lines by hypoxia was confirmed by altered morphology, expression change of EMT-associated markers and enhanced invasion capacity. We showed that hypoxia-induced EMT could be enhanced by addition of recombinant Wnt3a while it was repressed by -catenin small interfering RNA. An interaction between -catenin and hypoxia-induced factor-1 (hif-1) was found, and an underlying competition for -catenin between hif-1 and T-cell factor-4 was implied. Notably, increased hif-1 activity was accompanied with more significant EMT features. We also showed that the pro-EMT effect of -catenin in hypoxia was deprived in the absence of hif-1. Moreover, -catenin was found to be responsible for the maintenance of viability and proliferation for tumor cells undergoing hypoxia. We further showed a correlation between hif-1 and -catenin expression, and corresponding expression of EMT-associated markers in human HCC tissues. Our results suggest that Wnt/-catenin signaling enhances hypoxia-induced EMT in HCC by increasing the EMT-associated activity of hif-1 and preventing tumor cell death.