Putative role of hepatitis B virus X protein in hepatocarcinogenesis: Effects on apoptosis, DNA repair, mitogen‐activated protein kinase and JAK/STAT pathways

Abstract

The genome of HBV, as with other hepadnaviruses, is composed of circular, partly double-stranded DNA 5,6 ( Fig. 1).The long (minus) strand is approximately 3200 bases in length, and contains four open reading frames (ORF) that encode viral proteins and the cis-elements that are required for regulation of HBV gene expression and replication. 7 A plus strand of variable length maintains the circular structure of the genome by cohesive hybridization that straddles the 5¢ and 3¢ ends of the minus strand. Each ORF overlaps at least one other, and together they cover the entire genome. Thus, the cis-elements are included within the protein coding regions. This compact arrangement results in a highly economical utilization of the small genome. Abstract Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of hepatocellular carcinoma (HCC). The pathogenesis of HBV-induced malignant transformation is, however, incompletely understood. HBx, the protein encoded by the X open reading frame, is a transcriptional activator that has been implicated in hepatocarcinogenesis. HBx inhibits the function of the tumour suppressor protein p53 in what is thought to be an early event in hepatocyte transformation before the later accumulation of inactivating p53 point mutations. HBx inhibits apoptosis but also exerts pro-apoptotic effects. The effects of HBx on apoptosis may be important not only for the development of HCC but also for the establishment of HBV infection. Further implication of HBx in hepatocyte transformation has been the demonstration that it inhibits the repair of damaged hepatocyte DNA. This effect may be mediated by interaction with p53 or through binding to the damaged DNA binding protein (DDB), which plays an accessory role in nucleotide excision repair. In addition, HBx activates cell signalling cascades involving mitogen-activated protein kinase (MAPK) and Janus family tyrosine kinases (JAK)/signal transducer and activators of transcription (STAT) pathways. The implications of these modulating effects of HBx are not fully understood, but they are likely to have wide-ranging effects on hepatocyte proliferation, apoptosis and the regulation of cell growth checkpoints. The cellular functions ascribed to HBx are unusually diverse, and defining the biologically important role of HBx during HBV replication will go some way to understanding the sequelae of chronic HBV infection.

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

“…(Figure 6) Furthermore, by losing the proapoptotic ability, the mutant HBx enhanced the transforming ability of ras and myc (Tu et al, 2001). The abrogation of p53-mediated apoptosis by HBx (also reviewed by Arbuthnot et al, 2000;Bergsland, 2001;Murakami, 2001) may provide a selective clonal advantage for preneoplastic or neoplastic hepatocytes and contribute to hepatocellular carcinogenesis. Molecular epidemiological studies also support the hypothesis that mutant HBx integrated in HCC is positively associated with TP53 249 ser mutations.…”

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

“…HBx also appears to act as a paracrine factor (Tralhao et al, 2002). These various biologic effects have overlapping effects on cell proliferation and viability (Arbuthnot et al, 2000;Ahn et al, 2002). The results of studies varied, depending on the amount of HBx expressed in cells, the cell type utilized and their status of differentiation.…”

“…However, relevance of these interactions in an HBV infection model remained to be evaluated. In fact, according to the experimental conditions, HBx may act as a pro-or antiapoptotic protein (Arbuthnot et al, 2000). HBx has been shown to interact with p53, thereby inactivating several critical (Chun et al, 2003).…”

Hepatitis B virus X protein promotes liver cell proliferation via a positive cascade loop involving arachidonic acid metabolism and p-ERK1/2

“…Many studies suggest that the HBV X protein (HBx), encoded by the X gene, has a crucial role in the development of HCC [3]. HBx can also affect transcription, cell growth and apoptosis [4].…”