Putative roles of hepatitis B x antigen in the pathogenesis of chronic liver disease

Under most circumstances, hepatitis B virus (HBV) is noncytopathic. However, hepatocellular regeneration that accompanies each bout of hepatitis appears to be associated with increased integration of HBV DNA fragments expressing the virus encoded hepatitis B x antigen (HBxAg). Intrahepatic HBxAg staining correlates with the intensity and progression of chronic liver disease (CLD), and additional work has shown that HBxAg blocks immune mediated killing by Fas and by tumor necrosis factor alpha (TNFα). This is not only associated with the blockage of caspase activities by HBxAg, but also by the constitutive stimulation of hepatoprotective pathways, such as nuclear factor kappa B (NF-κB), phosphoinositol 3-kinase (PI3K), and beta-catenin (β-catenin). HBxAg also appears to promote fibrogenesis, by stimulating the production of fibronectin. HBxAg also stimulates the production and activity of transforming growth factor beta1 (TGFβ1) by several mechanisms, thereby promoting the profibrogenic and tumorigenic properties of this important cytokine. In addition, HBxAg appears to remodel the extracellular matrix (ECM) by altering the expression of several matrix metalloproteinases (MMPs), which may promote tumor metastasis. Hence, HBxAg appears to promote chronic infection by preventing immune mediated apoptosis of infected hepatocytes, by promoting the establishment and persistence of fibrosis and cirrhosis preceding the development of HCC, and by promoting the remodeling of EMC during tumor progression. © 2008 Elsevier Ireland Ltd. All rights reserved

HBV X protein: Elucidating a role in oncogenesis

Chronic HBV infection is associated with the development of hepatocellular carcinoma (HCC). HBV contributes to tumorigenesis by encoding hepatitis B x antigen (HBxAg), which is a trans-regulatory protein that appears to contribute to HCC by altering patterns of host gene expression. In this review, recent data is presented that outlines some of the putative mechanisms whereby HBxA9 contributes to HCC. With the development of animal models of HBxAg-mediated HCC, the relevance and temporal order of putative steps in this process can now be dissected to elucidate what is rate limiting and when. This will have a profound impact on the design of novel and specific therapeutics for HCC. © 2008 Future Medicine Ltd