Hepatitis B virus induces hypoxia-inducible factor-2α expression through hepatitis B virus X protein

Hu,Jian‑Li; Liu,Li‑Ping; Yang,Sheng‑Li; Fang,Xiefan; Wen,Lu; Ren,Quan‑Guang; Yu,Chao

doi:10.3892/or.2015.4480

Hepatitis B virus induces hypoxia-inducible factor-2α expression through hepatitis B virus X protein

Authors:
- Jian‑Li Hu
- Li‑Ping Liu
- Sheng‑Li Yang
- Xiefan Fang
- Lu Wen
- Quan‑Guang Ren
- Chao Yu
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Affiliations: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China, Department of Hepatobiliary and Pancreas Surgery, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong 518020, P.R. China, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA, Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550001, P.R. China
Published online on: December 8, 2015 https://doi.org/10.3892/or.2015.4480
Pages: 1443-1448

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Abstract

A growing number of studies suggest that the hepatitis B virus X protein (HBx) enhances the protein stability of the hypoxia-inducible factor-1α (HIF-1α). However, the relationship between hepatitis B virus (HBV), HBx and hypoxia-inducible factor-2α (HIF-2α) has not yet been fully elucidated. Immunohistochemical analysis was employed to detect the expression of HIF-2α in normal liver, HBV-related chronic hepatitis, and HBV-related and non-HBV-related hepatocellular carcinoma (HCC) tissues. Quantitative real‑time PCR (qPCR) and western blotting were used to investigate the impact of HBV and HBx on the expression of HIF‑2α. Immunoprecipitation and immunofluorescence were applied to explore the underlying mechanisms. The HIF‑2α expression was found to be higher in HBV‑related chronic hepatitis tissues than in normal liver tissues. Furthermore, it was higher in HBV‑related HCC tissues and HBV‑integrated HepG2 cells than in the corresponding non‑HBV‑related HCC tissues and HepG2 cells. Both HBV and HBx enhanced the protein stability of HIF‑2α. HBx‑mediated upregulation of HIF‑2α resulted mainly from an inhibition of the degradation of HIF‑2α due to the binding of HBx to the von Hippel‑Lindau protein (pVHL). In addition, HBx upregulated the expression of HIF‑2α by activating the NF‑κB signaling pathway. Thus, the present study identified that HBV induces the HIF‑2α expression through its encoded protein HBx. This upregulates the HIF-2α expression by binding to the pVHL activating the NF-κB signaling pathway.

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