Wnt/β-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1α signaling.
Epithelial-mesenchymal transition (EMT) is a critical process for tumor invasion and metastasis. Hypoxia may induce EMT, and upregulated β-catenin expression has been found in various tumors. In this study, we investigate the role of β-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 β-catenin small interfering RNA. An interaction between β-catenin and hypoxia-induced factor-1α (hif-1α) was found, and an underlying competition for β-catenin between hif-1α and T-cell factor-4 was implied. Notably, increased hif-1α activity was accompanied with more significant EMT features. We also showed that the pro-EMT effect of β-catenin in hypoxia was deprived in the absence of hif-1α. Moreover, β-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-1α and β-catenin expression, and corresponding expression of EMT-associated markers in human HCC tissues. Our results suggest that Wnt/β-catenin signaling enhances hypoxia-induced EMT in HCC by increasing the EMT-associated activity of hif-1α and preventing tumor cell death.
Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
Qi
Q
Zhang
Xueli
X
Bai
Wei
W
Chen
Tao
T
Ma
Qida
Q
Hu
Chao
C
Liang
Shangzhi
S
Xie
Conglin
C
Chen
Liqiang
L
Hu
Shiguo
S
Xu
Tingbo
T
Liang
D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D014746:Vimentin / Q000235:genetics / Q000378:metabolism; D060509:Wnt3A Protein / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
D015820:Cadherins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D014746:Vimentin; C555510:WNT3A protein, human; D060509:Wnt3A Protein; D051176:beta Catenin