Viral Hepatitis B

  • Mark A. Feitelson
  • Alla Arzumanyan
  • Helena M. G. P. V. Reis
  • Marcia M. Clayton
  • Bill S. Sun
  • Zhaorui Lian
Part of the Molecular Pathology Library book series (MPLB, volume 5)


Chronic hepatitis B virus (HBV) infection is the most important etiologic agent of hepatocellular carcinoma (HCC) worldwide. This is remarkable, considering that the virus consists of a DNA genome that is only 3.2 kb in size and encodes proteins from only four open reading frames (ORFs), all of which are located on the same DNA strand of the virus [1]. There are several morphological forms of HBV in the blood of infected patients. Most common is the small, spherical form, which is roughly 22 nm in diameter, and consists mainly of the hepatitis B surface antigen, or HBs envelope polypeptides embedded in the host-derived lipid membrane, derived from the infected cell. Less common are the variably long filamentous forms of HBs, which are also 22 nm in diameter, and have been found in the serum of infected patients. These forms are devoid of virus nucleic acid and are noninfectious, but are often present at very high concentrations. The virion of HBV, or Dane particle, is about 42 nm in diameter, is present in much lower concentrations than the subviral HBs particles mentioned above, and also consists of an envelope containing HBs polypeptides [2]. All HBs particles contain the major HBs protein and glycoprotein in roughly equal amounts, but virions also contain smaller quantities of HBs related polypeptides encoded by surface antigen plus adjacent upstream “preS” sequences encoded by the same ORF [1]. These so called preS/S polypeptides contain the virus-encoded receptor for infection, although the corresponding host-encoded receptor for HBV remains to be identified.


Chronic Liver Disease Infected Hepatocyte Chronic Carrier State Progressive Chronic Liver Disease Immune Mediate Apoptosis 


  1. 1.
    Tiollais P, Pourcel C, Dejean A. The hepatitis B virus. Nature. 1985;317:489–95.PubMedGoogle Scholar
  2. 2.
    Blumberg BS. Australia antigen and the biology of hepatitis B. Science. 1977;197:17–25.PubMedGoogle Scholar
  3. 3.
    Kramvis A, Kew MC. Structure and function of the encapsidation signal of hepadnaviridae. J Viral Hepat. 1998;5:357–67.PubMedGoogle Scholar
  4. 4.
    Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med. 2002;347:168–74.PubMedGoogle Scholar
  5. 5.
    Summers J, Mason WS. Replication of the genome of a hepatitis B – like virus by reverse transcription of an RNA intermediate. Cell. 1982;29:403–15.PubMedGoogle Scholar
  6. 6.
    Matsubara K, Tokino T. Integration of HBV DNA and its implications for hepatocarcinogenesis. Mol Biol Med. 1990;7:243–60.PubMedGoogle Scholar
  7. 7.
    Murakami Y, Saigo K, Takashima H, et al. Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas. Gut. 2005;54:1162–8.PubMedGoogle Scholar
  8. 8.
    Balsano C, Alisi A. Viral hepatitis B: established and emerging therapies. Curr Med Chem. 2008;15:930–9.PubMedGoogle Scholar
  9. 9.
    Chen DS. Hepatitis B vaccination: the key towards elimination and eradication of hepatitis B. J Hepatol. 2009;50:805–16.PubMedGoogle Scholar
  10. 10.
    Lai CL, Yuen MF. The natural history of chronic hepatitis B. J Viral Hepat. 2007;14 Suppl 1:6–10.PubMedGoogle Scholar
  11. 11.
    Hadziyannis SJ, Papatheodoridis GV. Hepatitis B e antigen-negative chronic hepatitis B: natural history and treatment. Semin Liver Dis. 2006;26:130–41.PubMedGoogle Scholar
  12. 12.
    Sun Z, Ming L, Zhu X, Lu J. Prevention and control of hepatitis B in China. J Med Virol. 2002;67:447–50.PubMedGoogle Scholar
  13. 13.
    Chang MH. Impact of hepatitis B vaccination on hepatitis B disease and nucleic acid testing in high-prevalence populations. J Clin Virol. 2006;36 Suppl 1:S45–50.PubMedGoogle Scholar
  14. 14.
    Rendi-Wagner P, Shouval D, Genton B, Lurie Y, Rumke H, Boland G, et al. Comparative immunogenicity of a PreS/S hepatitis B vaccine in non- and low responders to conventional vaccine. Vaccine. 2006;24:2781–9.PubMedGoogle Scholar
  15. 15.
    Chang MH. Cancer prevention by vaccination against hepatitis B. Recent Results Cancer Res. 2009;181:85–94.PubMedGoogle Scholar
  16. 16.
    Massad LS, Einstein M, Myers E, Wheeler CM, Wentzensen N, Solomon D. The impact of human papillomavirus vaccination on cervical cancer prevention efforts. Gynecologic Oncol. 2009;114:360–4.Google Scholar
  17. 17.
    Wilt TJ, Shamliyan T, Shaukat A, Taylor BC, MacDonald R, Yuan JM, et al. Management of chronic hepatitis B. Evid Rep Technol Assess. 2008;174:1–671.Google Scholar
  18. 18.
    Shamliyan TA, MacDonald R, Shaukat A, Taylor BC, Yuan JM, Johnson JR, et al. Antiviral therapy for adults with chronic hepatitis B: a systematic review for a National Institutes of Health Consensus Development Conference. Ann Int Med. 2009;150:111–24.PubMedGoogle Scholar
  19. 19.
    Alazawi W, Foster GR. Advances in the diagnosis and treatment of hepatitis B. Curr Opin Infect Dis. 2008;21:508–15.PubMedGoogle Scholar
  20. 20.
    Zoulim F, Perrillo R. Hepatitis B: reflections on the current approach to antiviral therapy. J Hepatol. 2008;48 Suppl 1:S2–19.PubMedGoogle Scholar
  21. 21.
    Batdelger D, Dandii D, Dahgwahdorj Y, Erdenetsogt E, Oyunbileg J, Tsend N, et al. Clinical experience with therapeutic vaccines designed for patients with hepatitis. Curr Pharmaceut Design. 2009;15:1159–71.Google Scholar
  22. 22.
    Parkin DM, Bray F, Ferlay J, PIsani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer. 2001;94:153–6.PubMedGoogle Scholar
  23. 23.
    Simonetti RG, Camma C, Fiorello F, Politi F, D’Amico G, Pagliaro L. Hepatocellular carcinoma. A worldwide problem and the major risk factors. Dig Dis Sci. 1991;36:962–72.PubMedGoogle Scholar
  24. 24.
    Gomaa AI, Khan SA, Leen EL, Waked I, Taylor-Robinson SD. Diagnosis of hepatocellular carcinoma. World J Gastroenterol. 2009;15:1301–14.PubMedGoogle Scholar
  25. 25.
    Block TM, Marrero J, Gish RG, Sherman M, London WT, Srivastava S, et al. The degree of readiness of selected biomarkers for the early detection of hepatocellular carcinoma: notes from a recent workshop. Cancer Biomark. 2008;4:19–33.PubMedGoogle Scholar
  26. 26.
    Okamoto K, Neureiter D, Ocker M. Biomarkers for novel targeted therapies of hepatocellular carcinoma. Histol Histopathol. 2009;24:493–502.PubMedGoogle Scholar
  27. 27.
    Calvisi DF, Pascale RM, Feo F. Dissection of signal transduction pathways as a tool for the development of targeted therapies of hepatocellular carcinoma. Rev Recent Clin Trials. 2007;2:217–36.PubMedGoogle Scholar
  28. 28.
    Lee CL, Hsieh KS, Ko YC. Trends in the incidenced of hepatocellular carcinoma in boys and girls in Taiwan after large-scale hepatitis B vaccination. Cancer Epidemiol Biomarkers Prev. 2003;12:57–9.PubMedGoogle Scholar
  29. 29.
    Feitelson MA. The pathogenesis of chronic hepatitis B virus infection. Bull Inst Pasteur. 1998;96:227–36.Google Scholar
  30. 30.
    Guidotti LG, Chisari FV. Immunobiology and pathogenesis of viral hepatitis. Ann Rev Pathol. 2006;1:23–61.Google Scholar
  31. 31.
    Katoh H, Shibata T, Kokubu A, et al. Epigenetic instability and chromosomal instability in hepatocellular carcinoma. Am J Pathol. 2006;168:1375–84.PubMedGoogle Scholar
  32. 32.
    Beasley RP, Hwang LY. Epidemiology of hepatocellular carcinoma. In: Vyas GN, Dienstag JL, Hoofnagle JH, editors. Viral hepatitis and liver disease. New York: Grune and Stratton; 1984. p. 209–24.Google Scholar
  33. 33.
    Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and HBV. A prospective study of 22, 707 men in Taiwan. Lancet. 1981;2:1129–32.PubMedGoogle Scholar
  34. 34.
    Ferrell LD, Crawford JM, Dhillon AP, Scheuer PJ, Nakanuma Y. Proposal for standardized criteria for the diagnosis of benign, borderline, and malignant hepatocellular lesions arising in chronic advanced liver disease. Am J Surg Pathol. 1993;17:1113–23.PubMedGoogle Scholar
  35. 35.
    Keasler VV, Hodgson AJ, Madden CR, Slagle BL. Enhancement of hepatitis B virus replication by the regulatory X protein in vitro and in vivo. J Virol. 2007;81:2656–62.PubMedGoogle Scholar
  36. 36.
    Feitelson MA, Duan LX. Hepatitis B virus x antigen in the pathogenesis of chronic infections and the development of hepatocellular carcinoma. Am J Pathol. 1997;150:1141–57.PubMedGoogle Scholar
  37. 37.
    Zhang X, Zhang H, Ye L. Effects of hepatitis B virus X protein on the development of liver cancer. J Lab Clin Med. 2006;147:58–66.PubMedGoogle Scholar
  38. 38.
    Huang J. Current progress in epigenetic research for hepatocarcinomagenesis. Sci China C Life Sci. 2009;52:31–42.PubMedGoogle Scholar
  39. 39.
    Boehme KW, Compton T. Innate sensing of viruses by toll-like receptors. J Virol. 2004;78:7867–73.PubMedGoogle Scholar
  40. 40.
    Lin S, Wu M, Xu Y, Xiong W, Zhang YZ, Zhenghong Y. Inhibition of hepatitis B virus replication by MyD88 is mediated by nuclear factor-kappaB activation. Biochim Biophys Acta. 2007;1772:1150–7.PubMedGoogle Scholar
  41. 41.
    Szabo G, Mandrekar P, Dolganiuc A. Innate immune response and hepatic inflammation. Semin Liver Dis. 2007;27:339–50.PubMedGoogle Scholar
  42. 42.
    Guidotti LG, Ishikawa T, Hobbs MV, et al. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity. 1996;4:25–36.PubMedGoogle Scholar
  43. 43.
    Chen Y, Wei H, Gao B, Hu Z, Zheng S, Tian Z. Activation and function of hepatic NK cells in hepatitis B infection: an underinvestigated innate immune response. J Viral Hepat. 2005;12:38–45.PubMedGoogle Scholar
  44. 44.
    Bonvin M, Greeve J. Hepatitis B: modern concepts in pathogenesis – APOBEC3 cytidine deaminases as effectors in innate immunity against the hepatitis B virus. Curr Opin Infect Dis. 2008;21:298–303.PubMedGoogle Scholar
  45. 45.
    Nicoll A, Locarnini S. Present and future directions in the treatment of chronic hepatitis B infection. J Gastroenterol Hepatol. 1997;12:843–54.PubMedGoogle Scholar
  46. 46.
    Wieland SF, Thimme R, Purcell RH, Chisari FV. Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci U S A. 2004;101:6669–74.PubMedGoogle Scholar
  47. 47.
    Wieland SF, Guidotti LG, Chisari FV. Intrahepatic induction of alpha/beta interferon eliminates viral RNA-containing capsids in hepatitis B virus transgenic mice. J Virol. 2000;74:4165–73.PubMedGoogle Scholar
  48. 48.
    Isogawa M, Robek MD, Furuichi Y, Chisari FV. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J Virol. 2005;79:7269–72.PubMedGoogle Scholar
  49. 49.
    Wu J, Lu M, Meng Z, et al. Toll-like receptor-mediated control of HBV replication by nonparenchymal liver cells in mice. Hepatology. 2007;46:1769–78.PubMedGoogle Scholar
  50. 50.
    Guo H, Jiang D, Ma D, et al. Activation of pattern recognition receptor-mediated innate immunity inhibits the replication of hepatitis B virus in human hepatocyte-derived cells. J Virol. 2009;83:847–58.PubMedGoogle Scholar
  51. 51.
    Wu J, Meng Z, Jiang M, et al. Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells. Hepatology. 2009;49:1132–40.PubMedGoogle Scholar
  52. 52.
    Kakimi K, Guidotti LG, Koezuka Y, et al. Natural killer T cells activation inhibits hepatitis B virus replication in vivo. J Exp Med. 2000;192:921–30.PubMedGoogle Scholar
  53. 53.
    Sitia G, Iaoqawa M, Kakimi K, et al. Depletion of neutrophils blocks the recruitment of antigen-nonspecific cells into the liver without affecting the antiviral activity of hepatitis B virus-specific cytotoxic T lmphocytes. Proc Natl Acad Sci U S A. 2002;99:13717–22.PubMedGoogle Scholar
  54. 54.
    Heike M, Rick K, Chisari FV, et al. Relative sensitivity of hepatitis B virus and other hepatotropic viruses to the antiviral effects of cytokines. J Virol. 2000;74:2255–64.Google Scholar
  55. 55.
    Chisari FV. Viruses, immunity and cancer: lessons from hepatitis B. Am J Pathol. 2000;156:1117–32.PubMedGoogle Scholar
  56. 56.
    Kimura K, Kakimi K, Wieland S, Guidotti LG, Chisari FV. Activated intrahepatic antigen-presenting cells inhibit hepatitis B virus replication in the liver of transgenic mice. J Immunol. 2002;169:5188–95.PubMedGoogle Scholar
  57. 57.
    Liu YJ. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol. 2005;23:275–306.PubMedGoogle Scholar
  58. 58.
    Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485–517.PubMedGoogle Scholar
  59. 59.
    Thimme R, Wieland S, Steiger C, et al. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol. 2003;77:68–76.PubMedGoogle Scholar
  60. 60.
    Gatta A, Giannini C, Lampertico P, et al. Hepatotropic viruses: new insights in pathogenesis and treatment. Clin Exp Rheumatol. 2008;26(1 Suppl 48):S33–8.PubMedGoogle Scholar
  61. 61.
    Billerbeck E, Bottler T, Thimme R. Regulatory T cells in viral hepatitis. World J Gastroenterol. 2007;13:4858–64.PubMedGoogle Scholar
  62. 62.
    Alatrakchi N, Koziel M. Regulatory T cells and viral liver disease. J Viral Hepat. 2009;16:223–9.PubMedGoogle Scholar
  63. 63.
    Zhang Z, Zhang JY, Wherry EJ, et al. Dynamic programmed death 1 expression by virus-specific CD8 T cells correlates with the outcome of acute hepatitis B. Gastroenterology. 2008;134:1938–49.PubMedGoogle Scholar
  64. 64.
    Zhang Z, Jin B, Zhang JY, et al. Dynamic decrease in PD-1 expression correlates with HBV-specific memory CD8 T-cell development in acute self-limited hepatitis B patients. J Hepatol. 2009;50:1163–73.PubMedGoogle Scholar
  65. 65.
    Isogawa M, Furuichi Y, Chisari FV. Oscillating CD8(+) T cell effector functions after antigen recognition in the liver. Immunity. 2005;23:53–63.PubMedGoogle Scholar
  66. 66.
    Maier H, Isogawa M, Freeman GJ, Chisari FV. PD-1:PD-L1 interactions contribute to the functional suppression of virus-specific CD8+ T lymphocytes in the liver. J Immunol. 2007;178:2714–20.PubMedGoogle Scholar
  67. 67.
    Ha SJ, West EE, Araki K, Smith KA, Ahmed R. Manipulating both the inhibitory and stimulatory immune system towards the success of therapeutic vaccination against chronic viral infections. Immunol Rev. 2008;223:317–33.PubMedGoogle Scholar
  68. 68.
    Kunitani H, Shimizu Y, Murata H, Higuchi K, Watanabe A. Phenotypic analysis of circulating and intrahepatic dendritic cell subsets in patients with chronic liver diseases. J Hepatol. 2002;36:734–41.PubMedGoogle Scholar
  69. 69.
    Tanimoto K, Akbar SM, Michitaka K, Horiike N, Onji M. Antigen-presenting cells at the liver tissue in patients with chronic viral liver diseases: CD83-positive mature dendritic cells at the vicinity of focal and confluent necrosis. Hepatol Res. 2001;21:117–25.PubMedGoogle Scholar
  70. 70.
    Nakamoto Y, Guidotti LG, Kuhlen CV, Fowler P, Chisari FV. Immune pathogenesis of hepatocellular carcinoma. J Exp Med. 1998;188:341–50.PubMedGoogle Scholar
  71. 71.
    Murray JM, Wieland SF, Purcell RH, Chisari FV. Dynamics of hepatitis B virus clearance in chimpanzees. Proc Natl Acad Sci U S A. 2005;102:17780–5.PubMedGoogle Scholar
  72. 72.
    Lopes AR, Kellam P, Das A, et al. Bim-mediated deletion of antigen-specific CD8 T cells in patients unable to control HBV infection. J Clin Invest. 2008;118:1835–45.PubMedGoogle Scholar
  73. 73.
    Elsaesser H, Sauer K, Brooks DG. IL-21 is required to control chronic viral infection. Science. 2009;324:1569–72.PubMedGoogle Scholar
  74. 74.
    Yi JS, Du M, Zajac AJ. A vital role for interleukin-21 in the control of a chronic viral infection. Science. 2009;324:1572–6.PubMedGoogle Scholar
  75. 75.
    Frohlich A, Kisielow J, Schmitz I, et al. IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science. 2009;324:1576–80.PubMedGoogle Scholar
  76. 76.
    Dejean A, Sonigo P, Wain-Hobson S, Tiollais P. Specific hepatitis B virus integration in hepatocellular carcinoma DNA through a viral 11-base-pair direct repeat. Proc Natl Acad Sci U S A. 1984;81:5350–4.PubMedGoogle Scholar
  77. 77.
    Poussin K, Kienes H, Sirma H, et al. Expression of mutated hepatitis B virus X genes in human hepatocellular carcinomas. Intl J Cancer. 1999;80:497–505.Google Scholar
  78. 78.
    Chen JY, Harrison TJ, Lee CS, Chen DS, Zuckerman AJ. Detection of hepatitis B virus DNA in hepatocellular carcinoma: analysis by hybridization with subgenomic DNA fragments. Hepatology. 1988;8:518–23.PubMedGoogle Scholar
  79. 79.
    Paterlini-Brechot P, Saigo K, Murakami Y, et al. Hepatitis B virus-related insertional mutagenesis occurs frequently in human liver cancers and recurrently targets human telomerase gene. Oncogene. 2003;22:3911–6.PubMedGoogle Scholar
  80. 80.
    Wang J, Chenivesse X, Henglein B, Brechot C. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature. 1990;343:555–7.PubMedGoogle Scholar
  81. 81.
    Feitelson MA, Lee JM. Hepatitis B virus integration, fragile sites, and hepatocarcinogenesis. Cancer Lett. 2007;252:157–70.PubMedGoogle Scholar
  82. 82.
    Kew MC. Hepatitis B and C viruses and hepatocellular carcinoma. Clin Lab Med. 1996;16:395–406.PubMedGoogle Scholar
  83. 83.
    Schluter V, Meyer M, Hofschneider PH, Koshy R, Caselmann WH. Integrated hepatitis B virus X and 3’ truncated preS/S sequences derived from human hepatomas encode functionally active transactivators. Oncogene. 1994;9:3335–44.PubMedGoogle Scholar
  84. 84.
    Yan PJ, Wang L, Zha XL, Lu CD. Activating effect of hepatitis B virus preS/S protein on proliferating cell nuclear antigen gene promoter. Chinese J Exp Clin Virol. 2003;17:42–5.Google Scholar
  85. 85.
    Herrmann G, Gregel C, Hubner K. Pathogenetic role of HBV in liver cell carcinoma of Western European patients. Verhandlungen Deutsch Gesellschaft Pathol. 1995;79:126–31.Google Scholar
  86. 86.
    Pollicino T, Campo S, Raimondo G. PreS and core gene heterogeneity in hepatitis B virus (HBV) genomes isolated from patients with long-lasting HBV chronic infection. Virology. 1995;208:672–7.PubMedGoogle Scholar
  87. 87.
    Diamantis ID, McGandy CE, Chen TJ, Liaw YF, Gudat F, Bianchi L. Hepatitis B X-gene expression in hepatocellar carcinoma. J Hepatol. 1992;15:400–3.PubMedGoogle Scholar
  88. 88.
    Paterlini P, Poussin K, Kew M, Franco D, Brechot C. Selective accumulation of the X transcript of HBV in patients negative for HBsAg with HCC. Hepatology. 1995;21:313–21.PubMedGoogle Scholar
  89. 89.
    Takada S, Koike K. Trans-activation function of a 30 truncated X gene-cell fusion product from integrated HBV DNA in chronic hepatitis tissues. Proc Natl Acad Sci U S A. 1990;87:5628–32.PubMedGoogle Scholar
  90. 90.
    Wollersheim M, Debelka U, Hofschneider PH. A trans-activating function encoded in the hepatitis B virus X gene is conserved in the integrated state. Oncogene. 1988;3:545–52.PubMedGoogle Scholar
  91. 91.
    Hohne M, Schaefer S, Seifer M, Feitelson MA, Paul D, Gerlich WH. Malignant transformation of immortalized hepatocytes by HBV DNA. EMBO J. 1990;9:1137–45.PubMedGoogle Scholar
  92. 92.
    Seifer M, Hohne M, Schaefer S, Gerlich WH. In vitro tumorigenicity of hepatitis B virus DNA and HBx protein. J Hepatol. 1991;13 Suppl 4:S61–5.PubMedGoogle Scholar
  93. 93.
    Kim CM, Koike K, Saito I, Miyamura T, Jay G. HBx gene of HBV induces liver cancer in transgenic mice. Nature. 1991;351:317–20.PubMedGoogle Scholar
  94. 94.
    Koike K, Moriya K, Iino S, et al. High level expression of hepatitis B virus HBx gene and hepatocarcinogenesis in transgenic mice. Hepatology. 1994;19:810–9.PubMedGoogle Scholar
  95. 95.
    Wang W, London WT, Lega L, Feitelson MA. HBxAg in liver from carrier patients with chronic hepatitis and cirrhosis. Hepatology. 1991;14:29–37.PubMedGoogle Scholar
  96. 96.
    Wang W, London WT, Feitelson MA. HBxAg in HBV carrier patients with liver cancer. Cancer Res. 1991;51:4971–7.PubMedGoogle Scholar
  97. 97.
    Henkler F, Koshy R. Hepatitis B virus transcriptional activators: mechanisms and possible role in oncogenesis. J Viral Hepat. 1996;3:109–21.Google Scholar
  98. 98.
    Ou DP, Tao YM, Tang FQ, Yang LY. The hepatitis B virus X protein promotes hepatocellular carcinoma metastasis by up-regulation of matrix metalloproteinases. Intl J Cancer. 2007;120:1208–14.Google Scholar
  99. 99.
    Ou DP, Tao YM, Chang ZG, Tang FQ, Yang LY. Hepatocellular carcinoma cells containing hepatitis B virus X protein have enhanced invasive potential conditionally. Digest Liver Dis. 2006;38:262–7.Google Scholar
  100. 100.
    Feitelson MA, Sun B, Tufan NL, Liu J, Pan J, Lian Z. Genetic mechanisms of hepatocarcinogenesis. Oncogene. 2002;21:2593–604.PubMedGoogle Scholar
  101. 101.
    Kondo Y, Kanai Y, Sakamoto M, Mizokami M, Ueda R, Hirohashi S. Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis – a comprehensive study of loss of heterzygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from patients with hepatocellular carcinoma. Hepatology. 2000;32:970–9.PubMedGoogle Scholar
  102. 102.
    Lee JO, Kwun HJ, Jung JK, Choi KH, Min DS, Jang KL. Hepatitis B virus X protein represses E-cadherin expression via activation of DNA methyltransferase 1. Oncogene. 2005;24:6617–25.PubMedGoogle Scholar
  103. 103.
    Liu J, Lian Z, Han S, et al. Down-regulation of E-cadherin by hepatitis B virus x antigen in hepatocellular carcinoma. Oncogene. 2006;25:1008–17.PubMedGoogle Scholar
  104. 104.
    Park IY, Sohn BH, Yu E, et al. Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein. Gastroenterology. 2007;132:1476–94.PubMedGoogle Scholar
  105. 105.
    Zheng SL, Zhang L, Cheng N, et al. Epigenetic modification induced by hepatitis B virus X protein via interaction with de novo DNA methyltransferase DNMT3A. J Hepatol. 2009;50:377–87.PubMedGoogle Scholar
  106. 106.
    Lu DD, Chen YC, Zhang XR, Cao XR, Jiang HY, Yao L. The relationship between metallothionein-1F (MT1F) gene and hepatocellular carcinoma. Yale J Biol Med. 2003;76:55–72.PubMedGoogle Scholar
  107. 107.
    Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE. The IL-4 receptor: signaling mechanisms and biological functions. Annu Rev Immunol. 1999;17:701–38.PubMedGoogle Scholar
  108. 108.
    Aoudjehand L, Podevin P, Scatton O, et al. Interkeukin-4 induces human hepatocyte apoptosis through a Fas-independent pathway. FASEB J. 2007;21:1433–44.Google Scholar
  109. 109.
    Pan J, Duan LX, Sun BS, Feitelson MA. Hepatitis B virus X protein decreases the anti-Fas induced apoptosis in human liver cells by inducing NF-κB. J Gen Virol. 2001;82(Part 1):171–82.Google Scholar
  110. 110.
    Pan J, Clayton MM, Feitelson MA. Hepatitis B x antigen promotes transforming growth factor β1 (TGFβ1) activity by up-regulation of TGFβ1 and down-regulation of alpha 2- macroglobulin. J Gen Virol. 2004;85:275–82.PubMedGoogle Scholar
  111. 111.
    Pan J, Lian Z, Wallett S, Feitelson MA. The hepatitis B x antigen effector, URG7, blocks tumor necrosis factor alpha mediated apoptosis by activation of phosphoinositol 3-kinase and β-catenin. J Gen Virol. 2007;88:3275–85.PubMedGoogle Scholar
  112. 112.
    Arora JJK, Pagano JS P, Jang KL. Expression of DNA methyltransferase 1 is activated by hepatitis B virus X protein via a regulatory circuit involving the p16INK4a-cyclin D1-CDK 4/6-pRb-E2F1 pathway. Cancer Res. 2007;67:5771–8.PubMedGoogle Scholar
  113. 113.
    Rouleau J, MacLeod AR, Szyf M. Regulation of the DNA methyl-transferase by the ras-AP-1 signaling pathway. J Biol Chem. 1995;270:1595–601.PubMedGoogle Scholar
  114. 114.
    Benn J, Schneider RJ. Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade. Proc Natl Acad Sci U S A. 1994;91:10350–4.PubMedGoogle Scholar
  115. 115.
    Benn J, Su F, Doria M, Schneider RJ. 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. 1996;70:4978–85.PubMedGoogle Scholar
  116. 116.
    Peterson EJ, Bogler O, Taylor SM. p53-mediated repression of DNA methyltransferase 1 expression by specific DNA binding. Cancer Res. 2003;63:6579–82.PubMedGoogle Scholar
  117. 117.
    Wong N, Lam WC, Lai PB, Pang E, Lau WY, Johnson PJ. Hypomethylation of chromosome 1 heterochromatin DNA correlates with q-arm gain in human hepatocellular carcinoma. Am J Pathol. 2001;159:465–71.PubMedGoogle Scholar
  118. 118.
    Herceg Z, Paliwal A. HBV protein as a double-barrel shot-gun targets epigenetic landscape in liver cancer. J Hepatol. 2009;50:252–5.PubMedGoogle Scholar
  119. 119.
    Calvisi DF, Ladu S, Gorden A, et al. Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. J Clin Invest. 2007;117:2713–22.PubMedGoogle Scholar
  120. 120.
    Aishima S, Basaki Y, Oda Y, et al. High expression of insulin-like growth factor binding protein-3 is correlated with lower portal invasion and better prognosis in human hepatocellular carcinoma. Cancer Sci. 2006;97:1182–90.PubMedGoogle Scholar
  121. 121.
    Hanafusa T, Shinji T, Shiraha H, et al. Functional promoter upstream p53 regulatory sequence of IGFBP3 that is silenced by tumor specific methylation. BMC Cancer. 2005;5:9–12.PubMedGoogle Scholar
  122. 122.
    Breuhahn K, Schirmacher P. Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma. World J Gastroenterol. 2008;14:1690–8.PubMedGoogle Scholar
  123. 123.
    Cougot D, Wu Y, Cairo S, et al. The hepatitis B virus X protein functionally interacts with CREB-binding protein/p300 in the regulation of CREB-mediated transcription. J Biol Chem. 2007;282:4277–87.PubMedGoogle Scholar
  124. 124.
    Shon JK, Shon BH, Park IY, et al. Hepatitis B virus-X protein recruits histone deacetylase 1 to repress insulin-like growth factor binding protein 3 transcription. Virus Res. 2009;139:14–21.PubMedGoogle Scholar
  125. 125.
    Vaissiere T, Sawan C, Herceg Z. Epigenetic interplay between histone modification and DNA methylation in gene silencing. Mutat Res. 2008;659:40–8.PubMedGoogle Scholar
  126. 126.
    Yoo YG, Na TY, Seo HW, et al. Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells. Oncogene. 2008;27:3405–13.PubMedGoogle Scholar
  127. 127.
    Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006;6:38–51.PubMedGoogle Scholar
  128. 128.
    Moon EJ, Jeong CH, Jeong JW, et al. Hepatitis B virus X protein induces angiogenesis by stabilizing hypoxia-inducible factor-1alpha. FASEB J. 2004;18:382–4.PubMedGoogle Scholar
  129. 129.
    Feitelson MA, Reis H, Pan J, et al. Abrogation of negative growth regulatory pathways by hepatitis B virus encoded X antigen in the development of hepatocellular carcinoma. In: Fleig WE, editor. Normal and malignant liver cell growth: FALK Workshop, vol. Chapter 15. Lancaster: Kluwer Academic; 1999. p. 156–70.Google Scholar
  130. 130.
    Yoo YD, Ueda H, Park K, et al. Regulation of transforming growth factor-β1 expression by the hepatitis B virus (HBV) X transactivator. J Clin Invest. 1996;97:388–95.PubMedGoogle Scholar
  131. 131.
    Shih WL, Kuo ML, Chuang SE, Cheng AL, Doong SL. Hepatitis B virus X protein inhibits transforming growth factor-β-induced apoptosis through the activation of phosphatidylinositol 3-kinase pathway. J Biol Chem. 2000;275:25858–64.PubMedGoogle Scholar
  132. 132.
    Akhurst RJ. TGF-beta antagonists: why suppress a tumor suppressor? J Clin Invest. 2002;109:1533–6.PubMedGoogle Scholar
  133. 133.
    Lee DK, Park SH, Yi Y, et al. The hepatitis B virus encoded oncoprotein pX amplifies TGF-β family signaling through direct interaction with Smad4: potential mechanism of hepatitis B virus-induced liver fibrosis. Genes Dev. 2001;15:455–66.PubMedGoogle Scholar
  134. 134.
    Kojima T, Takano K-I, Yamamoto T, et al. Transforming growth factor- β induces epithelial to mesenchymal transition by down-regulation of claudin-1 expression and the fence function in adult rat hepatocytres. Liver Intl. 2007;27:534–45.Google Scholar
  135. 135.
    Yang Y, Zheng L, Lv G, Jin X, Sheng J. Hepatocytes treated with HBV X protein as cytotoxic effectors kill primary hepatocytes by TNF-alpha-related apoptosis-induced ligand-mediated mechanism. Intervirology. 2007;50:323–7.PubMedGoogle Scholar
  136. 136.
    Herr I, Schemmer P, Buchler MW. On the TRAIL to therapeutic intervention in liver disease. Hepatology. 2007;46:266–74.PubMedGoogle Scholar
  137. 137.
    Su F, Schneider RJ. Hepatitis B virus HBx protein activates transcription factor NF-kappaB by acting on multiple cytoplasmic inhibitors of rel-related proteins. J Virol. 1996;70:4558–66.PubMedGoogle Scholar
  138. 138.
    Kekule AS, Lauer U, Weiss L, Luber B, Hofschneider PH. Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway. Nature. 1993;361:742–5.PubMedGoogle Scholar
  139. 139.
    Clippinger AJ, Gearhart TL, Bouchard MJ. Hepatitis B virus X protein modulates apoptosis in primary rat hepatocytes by regulating both NF-kappaB and the mitochondrial permeability transition pore. J Virol. 2009;83:4718–31.PubMedGoogle Scholar
  140. 140.
    Wang XW, Forrester K, Yeh H, Feitelson MA, Gu J, Harris CC. Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity and association with ERCC3. Proc Natl Acad Sci U S A. 1994;91:2230–4.PubMedGoogle Scholar
  141. 141.
    Jin YM, Yun C, Park C, Wang HJ, Cho H. Expression of hepatitis B virus X protein is closely correlated with the high periportal inflammatory activity of liver diseases. J Viral Hepat. 2001;8:322–30.PubMedGoogle Scholar
  142. 142.
    Kakimi K, Lane TE, Wieland S, et al. Blocking chemokine responsive to gamma-2/interferon (IFN)-gamma inducible protein and monokine induced by IFN-gamma activity in vivo reduces the pathogenetic but not the antiviral potential of hepatitis B virus-specific cytotoxic T lymphocytes. J Exp Med. 2001;194:1755–66.PubMedGoogle Scholar
  143. 143.
    Cheng J, Imanishi H, Morisake H, et al. Recombinant HBsAg inhibits LPS-induced COX-2 expression and IL-18 production by interfering with the NFkappaB pathways in a human monocytic cell line, THP-1. J Hepatol. 2005;43:465–71.PubMedGoogle Scholar
  144. 144.
    Visvanathan K, Skinner NA, Thompson AJ, et al. Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein. Hepatology. 2007;45:102–10.PubMedGoogle Scholar
  145. 145.
    Pasquetto V, Guidotti LG, Kakimi K, Tsuji M, Chisari FV. Host-virus interactions during malaria infection in hepatitis B virus transgenic mice. J Exp Med. 2000;192:529–36.PubMedGoogle Scholar
  146. 146.
    McClary H, Koch R, Chisari FV, Guidotti LG. Inhibition of hepatitis B virus replication during schistosoma mansoni infection in transgenic mice. J Exp Med. 2000;192:289–94.PubMedGoogle Scholar
  147. 147.
    Cavanaugh VJ, Guidotti LG, Chisari FV. Inhibition of hepatitis B virus replication during adenovirus and cytomegalovirus infections in transgenic mice. J Virol. 1998;72:2630–7.PubMedGoogle Scholar
  148. 148.
    Shishodia S, Aggarwal BB. Nuclear factor-kappaB activation: a question of life or death. J Biochem Mol Biol. 2002;35:28–40.PubMedGoogle Scholar
  149. 149.
    Beg AA, Baltimore D. An essential role for NFkB in preventing TNF-α-induced cell death. Science. 1996;274:782–4.PubMedGoogle Scholar
  150. 150.
    Beg A, Sha W, Bronson R, Ghosh S, Baltimore D. Embryonic lethality and liver regeneration in mice lacking the RelA component of NF-κ(kappa)B. Nature. 1995;376:167–70.PubMedGoogle Scholar
  151. 151.
    Chen R, Alvero AB, Silasi DA, Steffensen KD, Mor G. Cancers take their Toll – the function and regulation of Toll-like receptors in cancer cells. Oncogene. 2008;27:225–33.PubMedGoogle Scholar
  152. 152.
    Chung TW, Lee YC, Kim CH. Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential. FASEB J. 2004;18:1123–5.PubMedGoogle Scholar
  153. 153.
    Norton PA, Reis MGPV, Feitelson MA. Activation of fibronection gene expression by hepatitis B virus X antigen. J Viral Hepat. 2004;11:332–41.PubMedGoogle Scholar
  154. 154.
    Chen R, Alvero AB, Silasi DA, Mor G. Inflammation, cancer and chemoresistance: taking advantage of the toll-like receptor signaling pathway. Am J Reprod Immunol. 2007;57:93–107.PubMedGoogle Scholar
  155. 155.
    Pang LY, Argyle DJ. Using naturally occurring tumours in dogs and cats to study telomerase and cancer stem cell biology. Biochim Biophys Acta. 2009;1792:380–91.PubMedGoogle Scholar
  156. 156.
    Hiyama E, Hiyama K. Telomere and telomerase in stem cells. Br J Cancer. 2007;96:1020–4.PubMedGoogle Scholar
  157. 157.
    Campisi J. Cellular senescence as a tumor suppressor mechanism. Trends Cell Biol. 2001;11:S27–31.PubMedGoogle Scholar
  158. 158.
    Mathonnet G, Lachance S, Alaoui-Jamali M, Drobetsky EA. Expression of hepatitis B virus X oncoprotein inhibits transcription-coupled nucleotide excision repair in human cells. Mutat Res. 2004;554:305–18.PubMedGoogle Scholar
  159. 159.
    Jia L, Wang XW, Harris CC. Hepatitis B virus X protein inhibits nucleotide excision repair. Int J Cancer. 1999;80:875–9.PubMedGoogle Scholar
  160. 160.
    Oishi N, Shilagardi K, Nakamoto Y, Honda M, Kaneko S, Murakami S. Hepatitis B virus X protein overcomes oncogenic RAS-induced senescence in human immortalized cells. Cancer Sci. 2007;98:1540–8.PubMedGoogle Scholar
  161. 161.
    Yun C, Um HR, Jin YH, et al. NF-kappaB activation by hepatitis B virus X (HBx) protein shifts the cellular fate toward survival. Cancer Lett. 2002;184:97–104.PubMedGoogle Scholar
  162. 162.
    Harley CB, Futcher AB, Greider CW. Telomers shorten during aging of human fibroblasts. Nature. 1990;345:458–60.PubMedGoogle Scholar
  163. 163.
    Pascal T, Debacq-Chainlaux F, Chretien A, et al. Comparison of replicative senescence and stress-induced premature senescence combining differential display and low-density DNA arrays. FEBS Lett. 2005;579:3651–9.PubMedGoogle Scholar
  164. 164.
    Parinello S. Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol. 2003;5:839.Google Scholar
  165. 165.
    Ueda H, Ullrich SJ, Ngo L, et al. Functional inactivation but not structural mutation of p53 causes liver cancer. Nature Genet. 1995;9:41–7.PubMedGoogle Scholar
  166. 166.
    Sirma H, Giannini C, Poussin K, Paterlini P, Kremsforf D, Brechot C. Genetic and functional analysis of the effects of hepatitis B viral transactivator HBx on cell growth and apoptosis: implications for viral replication and hepatocarcinogenesis. In: Fleig WE, editor. Normal and malignant liver cell growth: FALK Workshop. Lancaster: Kluwer Academic; 1999. p. 171–86.Google Scholar
  167. 167.
    Wong OH et al. Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients. Cancer Res. 1999;59:71–3.PubMedGoogle Scholar
  168. 168.
    Qu ZL, Zou SQ, Cui NQ, et al. Upregulation of human telomerase reverse transcriptase mRNA expression by in vitro transfection of hepatitis B virus X gene into human hepatocarcinoma and cholangiocarcinoma cells. World J Gastroenterol. 2005;11:5627–32.PubMedGoogle Scholar
  169. 169.
    Zhang X, Dong N, Zhang H, You J, Wang H, Ye L. Effects of hepatitis B virus X protein on human telomerase reverse transcriptase expression and activity in hepatoma cells. J Lab Clin Med. 2005;145:98–104.PubMedGoogle Scholar
  170. 170.
    Benn J, Schneider RJ. HBV HBx protein deregulates cell cycle checkpoint controls. Proc Natl Acad Sci U S A. 1995;92:11215–9.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Mark A. Feitelson
    • 1
  • Alla Arzumanyan
  • Helena M. G. P. V. Reis
  • Marcia M. Clayton
  • Bill S. Sun
  • Zhaorui Lian
  1. 1.Department of BiologyTemple UniversityPhiladelphiaUSA

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