Haisheng Yu1, Mengqi Li1, Rui He1, Peining Fang1, Qiming Wang2, Yu Yi3, Fubing Wang4, Li Zhou5, Yi Zhang6, Aidong Chen7, Nanfang Peng1, Dan Liu8, Mirko Trilling9, Ruth Broering10, Erik A C Wiemer11, Mengji Lu9, Ying Zhu1, Shi Liu1. 1. State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China. 2. College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, China. 3. The Key Laboratory of Biosystems Homeostasis and Protection of the Ministry of Education and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China. 4. Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China. 5. Animal Biosafety Level III Laboratory at the Center for Animal Experiment, School of Medicine, Wuhan University, Wuhan, China. 6. Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, College of Food and Pharmaceutical Engineering, Hubei University of Technology, Wuhan, China. 7. Department of Physiology, Nanjing Medical University, Nanjing, China. 8. School of Basic Medical Science, Wuhan University, Wuhan, China. 9. Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 10. Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 11. Department of Medical Oncology, Erasmus University Medical Center Cancer Institute, Rotterdam, the Netherlands.
Abstract
BACKGROUND AND AIMS: Major vault protein (MVP) is up-regulated during infections with hepatitis B virus (HBV) and hepatitis C virus (HCV). Here, we found that MVP deficiency inhibited hepatocellular carcinoma (HCC) development induced by diethylnitrosamine, hepatitis B X protein, and HCV core. APPROACH AND RESULTS: Forced MVP expression was sufficient to induce HCC in mice. Mechanistic studies demonstrate that the ubiquitin ligase human double minute 2 (HDM2) forms mutual exclusive complexes either with interferon regulatory factor 2 (IRF2) or with p53. In the presence of MVP, HDM2 is liberated from IRF2, leading to the ubiquitination of the tumor suppressor p53. Mouse xenograft models showed that HBV and HCV promote carcinogenesis through MVP induction, resulting in a loss of p53 mediated by HDM2. Analyses of clinical samples from chronic hepatitis B, liver cirrhosis, and HCC revealed that MVP up-regulation correlates with several hallmarks of malignancy and associates with poor overall survival. CONCLUSIONS: Taken together, through the sequestration of IRF2, MVP promotes an HDM2-dependent loss of p53 that promotes HCC development.
BACKGROUND AND AIMS: Major vault protein (MVP) is up-regulated during infections with hepatitis B virus (HBV) and hepatitis C virus (HCV). Here, we found that MVP deficiency inhibited hepatocellular carcinoma (HCC) development induced by diethylnitrosamine, hepatitis B X protein, and HCV core. APPROACH AND RESULTS: Forced MVP expression was sufficient to induce HCC in mice. Mechanistic studies demonstrate that the ubiquitin ligase human double minute 2 (HDM2) forms mutual exclusive complexes either with interferon regulatory factor 2 (IRF2) or with p53. In the presence of MVP, HDM2 is liberated from IRF2, leading to the ubiquitination of the tumor suppressor p53. Mouse xenograft models showed that HBV and HCV promote carcinogenesis through MVP induction, resulting in a loss of p53 mediated by HDM2. Analyses of clinical samples from chronic hepatitis B, liver cirrhosis, and HCC revealed that MVP up-regulation correlates with several hallmarks of malignancy and associates with poor overall survival. CONCLUSIONS: Taken together, through the sequestration of IRF2, MVP promotes an HDM2-dependent loss of p53 that promotes HCC development.