MVP promotes hepatocellular carcinoma via targeting IRF2 and decreasing p53 activity

: Major vault protein (MVP) is up regulated during infections with hepatitis B and C virus. Here, we found that MVP deficiency inhibited hepatocellular carcinoma (HCC) development induced by di-ethyl-nitrosamine (DEN), HBx, and HCV Core. 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 presence of MVP, HDM2 is liberated from IRF2 leading to the ubiquitination of the tumor suppressor p53. Mouse xenograft models showed that Hepatitis B and C virus 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 upregulation correlates with several hallmarks of malignancy, and associates with poor overall survival. Taken together, through the sequestration of IRF2, MVP promotes an HDM2-dependent loss of p53 that promotes HCC development.