Do hepatitis B virus surface antigens have any role in viral carcinogenesis?

Do the hepatitis B virus (HBV) envelope proteins have any role in viral pathogenesis? This is a question that has dogged the hepatitis B research community since their discovery. HBV expresses three structurally related envelope proteins, designated as large (LHBs), middle (MHBs), and small (SHBs) surface proteins, from a single open reading frame (ORF; Fig. 1A). The SHBs protein is 226 amino acids (aa) in length, the MHBs has a Nterminal extension of 55 aa of the pre-S2 domain, and LHBs has the additional N-terminal extension of 108 aa of the pre-S1 domain. LHBs mediates binding of the virus to its receptor on hepatocytes. SHBs is the major component of viral envelope and subviral particles. Although a role for SHBs in induction of immune tolerance and carcinogenic activity for LHBs has been the subject of speculation for decades, the report from Yen et al., in this issue of HEPATOLOGY, provides circumstantial evidence for a role of LHBs and SHBs in hepatocarcinogenesis in humans. Specifically, analyses of LHBs and SHBs expression in tumor and adjacent liver tissues from 34 hepatocellular carcinoma (HCC) patients with chronic HBV infection by immunohistochemical staining (12 cases) and western blotting assays (22 cases) revealed that, compared to nontumorous tissue from the same patients, SHBs expression was greatly diminished in the tumors examined, whereas LHBs expression was not significantly decreased in the tumors of 95% patients. These data imply that while LHBs expression is maintained during HCC development, SHBs expression is lost or down-regulated. This is consistent with the previous findings that expression of either wild-type or pre-S2 mutant LHBs, in the absence of other viral proteins, is hepatocarcinogenic in mice. Taken together, the results support a hypothesis that, in the absence of SHBs expression, LHBs production may be cytopathic and pro-oncogenic, as illustrated in Fig. 1B. There is a growing literature regarding mutant HBV envelope proteins and their role in pathogenesis. Briefly, HBV variants with deletions in pre-S1 and/or pre-S2 regions have been reported to correlate with progression of liver disease in chronic HBV. Inframe deletions of the C-terminal pre-S1 region and the N-terminal pre-S2 region are the most common mutations found in HBV-infected individuals with advanced liver diseases and HCC. These regions contain multiple Tand B-cell epitopes, and their deletion might help the viruses to escape host antiviral immune responses. In a cohort of 175 HBV-related HCC patients, Yen et al. found that the increased peripheral blood levels of HBV mutants, with in-frame deletions in the pre-S2 region, are associated with elevated risk of HCC recurrence after curative hepatic resection. Expression of pre-S2 mutant LHBs was previously reported to be associated with type II ground glass hepatocytes, which are characterized by clustered nodule formations and suggested as preneoplastic lesions. Moreover, previous studies demonstrated that the misfolded pre-S2 mutant LHBs triggers endoplasmic reticulum (ER) stress-dependent DNA damage, disruption of cell-cycle progress, induction of Abbreviations: aa, amino acids; ER, endoplasmic reticulum; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; kb, kilobase; LHBs, large hepatitis B surface; MHBs, medium hepatitis B surface; ORF, open reading frame; SHBs, small hepatitis B surface.