Molecular Aspects of Hepatitis B Viral Infection and the Viral Carcinogenesis

  • Ryu, Wang-Shick (Department of Biochemistry and National Research Laboratory of Tumor Virology, Yonsei University)
  • Published : 2003.01.31


Of many viral causes of human cancer, few are of greater global importance than the hepatitis B virus (HBV). Over 250 million people worldwide are persistently infected with HBV. A significant minority of these develop severe pathologic consequences, including chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Earlier epidemiological evidence suggested a link between chronic HBV infection and HCC. Further, the existence of related animal viruses that induce acute and chronic infections of the liver, and eventually HCC, confirms the concept that HBV belongs to one of the few human oncogenic viruses. Although it is clear that chronic HBV infections are major risk factors, relatively little is understood about how the viral factors contribute to hepatocarcinogenesis. This review will introduce molecular aspects of the viral infection, and highlight recent findings on the viral contribution to hepatocarcinogenesis.


  1. Albritton, L. M., Tseng, L., Scadden. D. and Cunningham, J. M. (1989) A putative murine ecotropic retrovirus receptor gene encodes a multiple membrane-spanning protein and confers susceptibility to virus infection. Cell 57. 659-666.
  2. Beasley, R. P., Hwang. L. Y., Lin. C. C. and Chien. C. S. (1981) Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet 2. 1129-1133.
  3. Benn, J. and Schneider. R. J. (1994) Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf. MAP kinase signaling cascade. Proc. Natl. Acad. Sci. USA 91, 10350-10354.
  4. Benn, J. and Schneider, R. J. (1995) Hepatitis B virus HBx protein deregulates cell cycle checkpoint controls. Proc. Natl. Acad. Sci. USA 92, 11215-11219.
  5. Benn. J., Su, E, Doria, M. and Schneider, R. J. (1996) Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal-regulated and c-Jun N-terminal mitogen-activated protein kinases. J. Virol. 70, 4978-4985.
  6. Blum, H. E., Zhang, Z. S., Galun, E., von Weizsacker, F.,, Garner, B., Liang. T. J. and Wands. J. R. (1992) Hepatitis B virus X protein is not central to the viral life cycle in vitro. J. Virol. 66, 1223-1227.
  7. Bosch, V., Bartenschlager. R, Radziwill. G. and Schaller, H. (1988) The duck hepatitis B virus P-gene codes for protein strongly associated with the 5'-end of the viral DNA minus strand. Virology 166, 475-485.
  8. Bouchard. M. J., Wang. L. H. and Schneider, R. J. (2001) Calcium signaling by HBx protein in hepatitis B virus DNA replication. Science 294. 2376-2378.
  9. Brechot, C., Gozuacik. D., Murakami, Y. and Paterlini-Brechot, P. (2000) Molecular bases for the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Semin. Cancer BioI. 10, 211-231.
  10. Brechot, C., Pourcel, C., Louise. A., Rain. B. and Tiollais, P. (1980) Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma. Nature 286. 533-535.
  11. Buendia. M. A. (1992) Hepatitis B viruses and hepatocellular carcinoma. Adv. Cancer Res. 59, 167-226.
  12. Chen. H. S., Kaneko, S., Girones. R., Anderson, R. W., Hornbuckle, W. E., Tennant, B. C., Cote, P. J., Gerin. J. L., Purcell. R. H. and Miller, R. H. (1993) The woodchuck hepatitis virus X gene is important for establishment of virus infection in woodchucks. J. Virol. 67, 1218-1226.
  13. Chirillo, P.. Falco. M., Puri. P. L., Artini, M., Balsano. C., Levrero, M. and Natoli, G. (1996) Hepatitis B virus pX activates NF-kappa B-dependent transcription through a Raf-independent pathway. J. Virol. 70, 641-646.
  14. Chirillo. P., Pagano, S., Natoli, G., Puri, P. L., Burgio, V. L., Balsano, C. and Levrero, M. (1997) The hepatitis B virus X gene induces p53-mediated programmed cell death. Proc. Natl. Acad. Sci. USA 94, 8162-8167.
  15. Dalgleish, A. G., Beverley, P. C., Clapham, P. R. Crawford, D. H., Greaves, M. F. and Weiss, R. A. (1984) The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature 312, 763-767.
  16. Fourel, G., Couturier, J., Wei, Y., Apiou, F., Tiollais, P. and Buendia. M. A. (1994) Evidence for long-range oncogene activation by hepadnavirus insertion. EMBO J. 13, 2526-2534.
  17. Fourel, G., Trepo, C., Bougueleret, L., Hengiein, B., Ponzetto, A., TIoliais, P. and Buendia, M. A. (1990) Frequent activation of N-myc genes by hepadnavirus insertion in woodchuck liver tumors. Nature 347, 294-298.
  18. Ganem, D. (1982) Persistent infection of humans with hepatitis B virus: mechanisms and consequences. Rev. Infect. Dis. 4, 1026-1047.
  19. Ganem, D. Hepadnaviridae and Their Replication, 3rd ed. Lippincott-Raven Publishers, Philadelphia.
  20. Ganem, D. (2001) Virology. The X files--one step closer to closure. Science 294, 2299-2300.
  21. Ganem, D., Greenbaum, L. and Varmus, H. E. (1982) Virion DNA of ground squirrel hepatitis virus: structural analysis and molecular cloning. J. Virol. 44, 374-383.
  22. Ganem, D. and Varmus, H. E. (1987) The molecular biology of the hepatitis B viruses. Annu. Rev. Biochem. 56,651-693.
  23. Guidotti, L. G., Matzke, B., Schaller, H. and Chisari, F. V. (1995) High-level hepatitis B virus replication in transgenic mice. J. Virol. 69, 6158-6169.
  24. Havert, M. B. and Loeb, D. D. (1997) cis-Acting sequences in addition to donor and acceptor sites are required for template switching during synthesis of plus-strand DNA for duck hepatitis B virus. J. Virol. 71, 5336-5344.
  25. Hirsch, R. C., Loeb, D. D., Pollack, J. R and Ganem, D. (1991) cis-acting sequences required for encapsidation of duck hepatitis B virus pregenomic RNA. J. Virol. 65, 3309-3316.
  26. Hohne, M., Schaefer, S., Seifer, M., Feitelson, M. A., Paul, D. and Gerlich, W. H. (1990) Malignant transformation of immortalized transgenic hepatocytes after transfection with hepatitis B virus DNA. EMBO J. 9, 1137-1145.
  27. Jeong, J. K., Yoon, G. S. and Ryu, W. S. (2000) Evidence that the 5'-end cap structure is essential for encapsidation of hepatitis B virus pregenomic RNA. J. Virol. 74, 5502-5508.
  28. Junker-Niepmann, M., Bartenschlager, R. and Schaller, H. (1990) A short cis-acting sequence is required for hepatitis B virus pregenome encapsidation and sufficient for packaging of foreign RNA. EMBO J. 9, 3389-3396.
  29. Kim, C. M., Koike, K, Saito. J., Miyamura, T. and Jay. G. (1991) HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 351, 317-320.
  30. Kim, H., Lee, H. and Yun, Y. (1998) X-gene product of hepatitis B virus induces apoptosis in liver cells. J. Biol. Chem. 273, 381-385.
  31. Kim, Y. C., Song, K. S., Yoon, G., Nam. M. J. and Ryu, W. S. (2001) Activated ras oncogene collaborates with HBx gene of hepatitis B virus to transform cells by suppressing HBx-mediated apoptosis. Oncogene 20, 16-23.
  32. Klein, N. P. and Schneider, R J. (1997) Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras. Mol. Cell. Biol. 17,6427-6436.
  33. Koike, K, Moriya, K, lino, S., Yotsuyanagi, H., Endo, Y., Miyamura, T. and Kurokawa, K. (1994a) High-level expression of hepatitis B virus HBx gene and hepatocarcinogenesis in transgenic mice. Hepatology 19, 810-819.
  34. Koike, K., Moriya, K., Yotsuyanagi, H., lino, S. and Kurokawa, K. (1994b) Induction of cell cycle progression by hepatitis B virus HBx gene expression in quiescent mouse fibroblasts. J. Clin. Invest. 94, 44-49.
  35. Kuroki, K., Cheung, R., Marion, P. L. and Ganem, D. (1994) A cell surface protein that binds avian hepatitis B virus particles. J. Virol. 68, 2091-2096.
  36. Kuroki, K., Eng, F., Ishikawa, T., Turck, C., Harada, F. and Ganem, D. (1995) gp180, a host cell glycoprotein that binds duck hepatitis B virus particles, is encoded by a member of the carboxypeptidase gene family. J. BioI. Chem. 270, 15022-15028.
  37. Lucito, R. and Schneider, R J. (1992) Hepatitis B virus X protein activates transcription factor NF-kappa B without a requirement for protein kinase C. J Virol. 66, 983-991.
  38. Marion, P. L., Salazar, F. H., Alexander, J. J. and Robinson, W. S. (1980) State of hepatitis B viml DNA in a human hepatoma cell line. J. Virol. 33, 795-806.
  39. Marion, P. L., Van Davelaar, M. J., Knight, S. S., Salazar, F. H., Garcia, G., Popper, H. and Robinson, W. S. (1986) Hepatocellular carcinoma in ground squirrels persistently infected with ground squirrel hepatitis virus. Proc. Natl. Acad. Sci. USA 83, 4543-4546.
  40. Murakami, S. (200l) Hepatitis B virus X protein: a multifunctional viral regulator. J Gastroenterol. 36, 651-660.
  41. Nassal, M. (1996) Hepatitis B virus morphogenesis. Curr. Top. Microbiol. lmmunol. 214, 297-337.
  42. Nassal, M. (2002) $Ca^{2+}$: the clue to hepatitis B virus X protein function? Hepatology 36, 755-757.
  43. Nassal, M. and Schaller, H. (1996) Hepatitis B virus replication-- anupdate. J. Viral. Hepat. 3, 217-226.
  44. Natoli, G., Avantaggiati, M. L., Chirillo, P., Puri, P. L., Ianni, A., Balsano, C. and Levrero, M. (1994) Ras- and Raf-dependent activation of c-jun transcriptional activity by the hepatitis B virus transactivator pX. Oncogene 9, 2837-2843.
  45. Oguey, D., Dumenco, L. L., Pierce, R. H. and Fausto, N. (1996) Analysis of the tumorigenicity of the X gene of hepatitis B virus in a non-transformed hepatocyte cell line and the effects of co-transfection with a murine p53 mutant equivalent to human codon 249. Hepatology 24, 1024-1033.
  46. Popper, H., Roth, L., Purcell, R. H., Tennant, B. C. and Gerin, J. L. (1987) Hepatocarcinogenicity of the woodchuck hepatitis virus. Proc. Natl. Acad. Sci. USA 84, 866-870.
  47. Popper, H., Shih, J. W, Gerin, J. L., Wong, D. C., Hoyer, B. H., London, W. T., Sly, D. L. and Purcell, R H. (1981) Woodchuck hepatitis and hepatocellular carcinoma: correlation of histologic with virologic observations. Hepatology 1, 91-98.
  48. Protzer, U., Nassal, M., Chiang, P. W., Kirschfink, M. and Schaller, H. (1999) Interferon gene transfer by a hepatitis B virus vector efficiently suppresses wild-type virus infection. Proc. Natl. Acad. Sci. USA 96, 10818-10823.
  49. Rogier, C. E., Sherman, M., Su, C. Y., Shafritz, D. A., Summers, J., Shows, T. B., Henderson, A. and Kew, M. (1985) Deletion in chromosome 11p associated with a hepatitis B integration site in hepatocellular carcinoma. Science 230, 319-322.
  50. Seeger, C. and Mason, W. S. (2000) Hepatitis B virus biology. Microbiol. Mol. Biol. Rev. 64,51-68.
  51. Shirakata, Y., Kawada, M., Fujiki, Y., Sano, H., Oda, M., Yaginuma, K., Kobayashi, M. and Koike, K. (1989) The X gene of hepatitis B virus induced growth stimulation and tumorigenic transformation of mouse NIH3T3 cells. Jpn. J. Cancer. Res. 80, 617-621.
  52. Su, F. and Schneider, R. J. (1996) Hepatitis B virus HBx protein activates transcription factor NF-kappaB by acting on multiple cytoplasmic inhibitors of reI-related proteins. J. Virol. 70, 4558- 4566.
  53. Summers, J. and Mason, W. S. (1982) Replication of the genome of a hepatitis B--like virus by reverse transcription of an RNA intermediate. Cell 29, 403-415.
  54. Tam, C., Bilodeau, M. L., Hullinger, R. L. and Andrisani, O. M. (1999) Differential immediate early gene expression in conditional hepatitis B virus pX-transforming versus nontransforming hepatocyte cell lines. J. Biol. Chem. 274, 2327-2336.
  55. Terradillos, O., Billet, O., Renard, C. A., Levy, R., Molina, T., Briand, P. and Buendia, M. A. (1997) The hepatitis B virus X gene potentates c-myc-induced liver oncogenesis in transgenic mice. Oncogene 14, 395-404.
  56. Tong, S., Li, J. and Wands, J. R. (1995) Interaction between duck hepatitis B virus and a 170-kilodalton cellular protein is mediated through a neutralizing epitope of the pre- S region and occurs during viral infection. J. Virol. 69,7106-7112.
  57. Urban, S., Breiner, K. M., Fehler, F., Klingmuller, U. and Schaller, H. (1998) Avian hepatitis B virus infection is initiated by the interaction of a distinct pre-S subdomain with the cellular receptor gp180. J. Virol. 72, 8089-8097.
  58. Wang, G. H. and Seeger, C. (1992) The reverse transcriptase of hepatitis B virus acts as a protein primer for viral DNA synthesis. Cell 71, 663-670.
  59. Yaginuma, K., Kobayashi, M., Yoshida, E. and Koike, K. (1985) Hepatitis B virus integration in hepatocellular carcinoma DNA: duplication of cellular flanking sequences at the integration site. Proc. Natl. Acad. Sci. USA 82, 4458-4462.
  60. Yen, T. S. B. (1996) Hepadnaviral X protein: review of recent progress. J. Biomed. Sci. 3, 20-30.
  61. Young, J. A., Bates, P. and Varmus, H. E. (1993) Isolation of a chicken gene that confers susceptibility to infection by subgroup A avian leukosis and sarcoma viruses. J. Virol. 67, 1811-1816.
  62. Zoulim, F., Saputelli, J. and Seeger, C. (1994) Woodchuck hepatitis virus X protein is required for viral infection in vivo. J. Virol. 68, 2026-2030.

Cited by

  1. Human oncogenic viruses: Hepatitis B and hepatitis C viruses and their role in hepatocarcinogenesis vol.73, pp.5, 2008,
  2. Occult hepatitis B viral DNA in liver carcinomas from a region with a low prevalence of chronic hepatitis B infection vol.11, pp.4, 2004,
  3. Hepatocellular carcinoma: role of hepatitis B and hepatitis C viruses proteins in hepatocarcinogenesis vol.11, pp.5, 2004,
  4. Expression of the PreS1 Peptide of Hepatitis B Virus and Preparation of Its Polyclonal Antibody vol.30, pp.6, 2011,
  5. Hepatitis D–related Cirrhosis and Risk of Hepatocellular Carinoma Development vol.233, pp.1, 2004,
  6. Hepatitis B Virus X Upregulates HuR Protein Level to Stabilize HER2 Expression in Hepatocellular Carcinoma Cells vol.2014, 2014,
  7. Expression and purification of the synthetic preS1 gene of Hepatitis B Virus with preferred Escherichia coli codon preference vol.48, pp.1, 2006,
  8. Pathogenesis of hepatitis B virus infection vol.1, pp.5, 2006,