Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx

Abstract

Chronic infection by HBV is the leading cause of hepatocellular carcinoma in man. Several lines of evidence suggest that the viral transactivator HBx plays a critical role in the molecular pathogenesis of HBVrelated HCC. To study the actual impact of HBx and the mechanism of its action, we have recently cloned and characterized a set of X-sequences from HCC in patients with chronic infection by HBV. In the present study, we have compared the e ects of HBx and its naturally arising mutants on cell growth and viability. We report that HBx inhibits clonal outgrowth of cells and induces apoptosis by a p53-independent pathway. Furthermore, HBx expression induced a late G1 cell cycle block prior to their counterselection by apoptosis. Importantly, mutations in the HBx-gene evolving in hepatocellular carcinoma abolished both HBx-induced growth arrest and apoptosis. Using a panel of engineered mutants we have mapped the growth suppressive e ect of HBx to domains shown to be required for its transactivating function. Based on these results, we propose that abrogation of the anti-proliferative and apoptotic e ects of HBx by naturally occurring mutations might render the hepatocytes susceptible to uncontrolled growth and contribute to multistep hepatocarcinogenesis associated with HBV-infection.

Hepatitis B virus X protein mutant upregulates CENP-A expression in hepatoma cells

“…Ours and other previous findings have shown that different domains at HBx-COOH may represent various mechanisms, and the mutations may directly affect the proliferation and invasion by regulating the cell cycle and inducing the expression of p21 WAF1 , p14 ARF and MDM2 (13). This supports the hypothesis that deleted forms of HBx may contribute to liver carcinogenesis (13,(30)(31)(32). Our previous findings also demonstrated that CENP-A overexpression was correlated with serum HBsAg states in HCC patients (16).…”

TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer

“…Moreover, HBx deregulates cell cycle check point controls and blocks p53-mediated apoptosis (Lucito and Schneider, 1992;Feitelson et al, 1993;Bennett et al, 1995;Wang et al, 1995;Miura et al, 1997;Chan and Ng, 2006). Interestingly, tumorderived HBx mutants that lacked their transcriptional cotransactivation activity as well as proapoptotic activity (Sirma et al, 1999), still retained their p53-binding functions and blocked p53-mediated apoptosis (Huo et al, 2001. (Figure 6) Furthermore, by losing the proapoptotic ability, the mutant HBx enhanced the transforming ability of ras and myc (Tu et al, 2001).…”

Hepatitis B Virus Gene C1653T Polymorphism Mutation and Hepatocellular Carcinoma Risk: an Updated Meta-analysis

“…Indeed, codon 94 (nt 1653 to 1655) is within the function domain of the X protein, which has been reported to play a central role in transactivation (Kumar et al, 1996). And the C1653T mutation might enhance the binding affinity of related factors and enhancer II/core promoter activity, cause activation of an indolent immune response, as well as abrogates both the antiproliferative and transactivation effects of wildtype HBx (Lee et al, 1998;Sirma et al, 1999).These changes may be involved in hepatocarcinogenesis.…”