Downregulation and pro-apoptotic effect of hypoxia-inducible factor 2 alpha in hepatocellular carcinoma
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Sheng-li Yang1,2,*, Li-ping Liu3,*, Leilei Niu1, Yun-fan Sun4, Xing-rong Yang4, Jia Fan4, Jian-wei Ren1,2, George G. Chen1,2, Paul B.S. Lai1
1Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China
2Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
3Department of Hepatobiliary and Pancreas Surgery, The Second Clinical Medical College of Jinan University (Shenzhen People’s Hospital), Shenzhen, Guangdong, China
4Department of Liver Surgery, Zhongshan Hospital & Liver Cancer Institute, Fudan University, Shanghai, China
*These authors have contributed equally to this work
George G. Chen, e-mail: [email protected]
Paul B.S. Lai, e-mail: [email protected]
Keywords: hepatocellular carcinoma, HIF-2α, overall survival, prognosis, apoptosis
Received: September 22, 2015 Accepted: April 10, 2016 Published: April 23, 2016
The role of HIF-2α in hepatocellular carcinoma (HCC) is unclear. The aim of the present study was to investigate the expression pattern and role of HIF-2α in HCC patients. Immunohistochemical staining and western blotting analyses were applied to detect the protein level of HIF-2α in 206 paired HCC and peritumoral tissues. Kaplan-Meier survival and Cox proportional hazard regression analyses were performed to identify risk factors for overall survival and recurrence-free survival in these patients. The function of HIF-2α was studied in HCC cells and in vivo models. We found that the protein levels of HIF-2α in HCC tissues were lower than in peritumoral tissues, and were negatively correlated with tumor size (P < 0.05). Kaplan-Meier survival and univariate analysis revealed that HCC patients with high HIF-2α protein levels had longer overall survival (P < 0.05). Over-expression of HIF-2α induced apoptosis in HCC cells and increased the levels of pro-apoptotic proteins, Bak, ZBP-89 and PDCD4, whereas the inhibition of HIF-2α expression achieved opposite results. The findings were confirmed in a mouse HCC xenograft model. In conclusion, our study revealed that HIF-2α was decreased and played an anti-tumorigenic role in HCC.
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