Hepatitis B virus and hepatocellular carcinoma

Abstract

Chronic hepatitis B virus (HBV) infection is a major global cause of hepatocellular carcinoma (HCC). Individuals who are chronic carriers have a greater than 100-fold increased relative risk of developing the tumour. Several mechanisms of HBV-induced HCC have been proposed. Integration of HBV DNA into the genome of hepatocytes occurs commonly, although integration at cellular sites that are important for regulation of hepatocyte proliferation appears to be a rare event. Functions of the HBx protein are also potentially oncogenic. These include transcriptional activation of cellular growth regulatory genes, modulation of apoptosis and inhibition of nucleotide excision repair of damaged cellular DNA. The effects of HBx are mediated by interaction with cellular proteins and activation of cell signalling pathways. Variations in HBV genome sequences may be important in hepatocarcinogenesis, although their significance has not yet been completely elucidated. Necroinflammatory hepatic disease, which often accompanies chronic HBV infection, may contribute indirectly to hepatocyte transformation in a number of ways, including by facilitating HBV DNA integration, predisposing to the acquisition of cellular mutations and generating mutagenic oxygen reactive species. Although HCC is a malignancy with a poor prognosis, the availability of an effective vaccine against HBV infection, and its inclusion in the Expanded Programme of Immunization of many countries, augurs well for the eventual elimination of HBV-associated HCC.

Specific mutations of hepatitis B virus in plasma predict liver cancer development

“…The development of new biomarkers for predicting an individual's risk for HCC after HBV infection is predicated on an understanding of the molecular pathways through which the virus mediates its effects (5,7,30). The pathobiology of HBV infection is also modulated through the selection and expression of a number of common viral mutants that affect a number of key viral proteins (8,9,31,32).…”

“…HBV is a significant risk factor for HCC in the developing world, where there are Ͼ400 million viral carriers (5,6). The biology, mode of transmission, and epidemiology of this virus continue to be actively investigated and have been recently reviewed (5,6).…”

“…The biology, mode of transmission, and epidemiology of this virus continue to be actively investigated and have been recently reviewed (5,6). The contribution of HBV to the pathogenesis of liver cancer is multifactorial and is complicated by the identification of mutant variants in HBV that modulate the carcinogenesis process (7)(8)(9).…”

“…The HBV genome encodes its essential genes with overlapping ORFs; therefore, a mutation in the HBV genome can alter the expression of multiple proteins. In many cases of HCC in China and Africa, a double mutation in the HBV genome, an adenine-to-thymine transversion at nucleotide 1762 and a guanine-to-adenine transition at nucleotide 1764 (1762 T ͞ 1764 A ), has been found in tumors (5,10,11). This segment of the HBV genome contains an overlapping sequence for the base core promoter and the HBV X gene; therefore, the double mutation in codons 130 and 131 of the HBV X gene reported in human HCC is identical to the 1762 and 1764 nucleotide changes (12,13).…”

Caspase-dependent Alterations of Ca2+ Signaling in the Induction of Apoptosis by Hepatitis B Virus X Protein

“…Among the proteins encoded by the HBV genome, the X protein (HBx) has been shown to have a central role in HBV replication and a potential role in liver oncogenesis (2,3). Overexpression of HBx induces transformation of some cell types (4,5).…”