Skip to main content

Advertisement

Log in

Hepatitis B virus X gene and hepatocarcinogenesis

  • Review
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Chronic hepatitis B virus (HBV) infection has been identified as a major risk factor in hepatocellular carcinoma (HCC), which is one of the most common cancers worldwide. The pathogenesis of HBV-mediated hepatocarcinogenesis is, however, incompletely understood. Evidence suggests that the HBV X protein (HBx) plays a crucial role in HCC development. HBx is a multifunctional regulator that modulates transcription, signal transduction, cell cycle progression, apoptosis, protein degradation pathways, and genetic stability through interaction with host factors. This review describes the current state of knowledge of the molecular pathogenesis of HBV-induced HCC, with a focus on the role of HBx in hepatocarcinogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004;127(5 Suppl 1):S5–16.

    Article  PubMed  Google Scholar 

  2. Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. Eur J Cancer. 2001;37(Suppl 8):S4–66.

    Article  PubMed  Google Scholar 

  3. Montalto G, Cervello M, Giannitrapani L, Dantona F, Terranova A, Castagnetta LA. Epidemiology, risk factors, and natural history of hepatocellular carcinoma. Ann NY Acad Sci. 2002;963:13–20.

    Article  PubMed  Google Scholar 

  4. Hassan MM, Hwang LY, Hatten CJ, Swaim M, Li D, Abbruzzese JL, et al. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology. 2002;36(5):1206–13.

    Article  PubMed  CAS  Google Scholar 

  5. 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(3):168–74.

    Article  PubMed  CAS  Google Scholar 

  6. Azam F, Koulaouzidis A. Hepatitis B virus and hepatocarcinogenesis. Ann Hepatol. 2008;7(2):125–9.

    PubMed  CAS  Google Scholar 

  7. Bosch FX, Ribes J, Cleries R, Diaz M. Epidemiology of hepatocellular carcinoma. Clin Liver Dis. 2005;9(2):191–211, v.

    Google Scholar 

  8. Clevers H. At the crossroads of inflammation and cancer. Cell. 2004;118(6):671–4.

    Article  PubMed  CAS  Google Scholar 

  9. 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(5):322–30.

    Article  PubMed  CAS  Google Scholar 

  10. Bonilla Guerrero R, Roberts LR. The role of hepatitis B virus integrations in the pathogenesis of human hepatocellular carcinoma. J Hepatol. 2005;42(5):760–77.

    Article  PubMed  CAS  Google Scholar 

  11. Chami M, Gozuacik D, Saigo K, Capiod T, Falson P, Lecoeur H, et al. Hepatitis B virus-related insertional mutagenesis implicates SERCA1 gene in the control of apoptosis. Oncogene. 2000;19(25):2877–86.

    Article  PubMed  CAS  Google Scholar 

  12. Hytiroglou P, Theise ND. Telomerase activation in human hepatocarcinogenesis. Am J Gastroenterol. 2006;101(4):839–41.

    Article  PubMed  CAS  Google Scholar 

  13. Minami M, Daimon Y, Mori K, Takashima H, Nakajima T, Itoh Y, et al. Hepatitis B virus-related insertional mutagenesis in chronic hepatitis B patients as an early drastic genetic change leading to hepatocarcinogenesis. Oncogene. 2005;24(27):4340–8.

    Article  PubMed  CAS  Google Scholar 

  14. Murakami Y, Saigo K, Takashima H, Minami M, Okanoue T, Brechot C, et al. Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas. Gut. 2005;54(8):1162–8.

    Article  PubMed  CAS  Google Scholar 

  15. Paterlini-Brechot P, Saigo K, Murakami Y, Chami M, Gozuacik D, Mugnier C, et al. Hepatitis B virus-related insertional mutagenesis occurs frequently in human liver cancers and recurrently targets human telomerase gene. Oncogene. 2003;22(25):3911–6.

    Article  PubMed  CAS  Google Scholar 

  16. Wang J, Chenivesse X, Henglein B, Brechot C. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature. 1990;343(6258):555–7.

    Article  PubMed  CAS  Google Scholar 

  17. Wang P, Wang X, Cong S, Ma H, Zhang X. Mutation analyses of integrated HBV genome in hepatitis B patients. J Genet Genomics. 2008;35(2):85–90.

    Article  PubMed  Google Scholar 

  18. Arbuthnot P, Capovilla A, Kew M. Putative role of hepatitis B virus X protein in hepatocarcinogenesis: effects on apoptosis, DNA repair, mitogen-activated protein kinase and JAK/STAT pathways. J Gastroenterol Hepatol. 2000;15(4):357–68.

    Article  PubMed  CAS  Google Scholar 

  19. Diao J, Khine AA, Sarangi F, Hsu E, Iorio C, Tibbles LA, et al. X protein of hepatitis B virus inhibits Fas-mediated apoptosis and is associated with up-regulation of the SAPK/JNK pathway. J Biol Chem. 2001;276(11):8328–40.

    Article  PubMed  CAS  Google Scholar 

  20. Kekule AS, Lauer U, Meyer M, Caselmann WH, Hofschneider PH, Koshy R. The preS2/S region of integrated hepatitis B virus DNA encodes a transcriptional transactivator. Nature. 1990;343(6257):457–61.

    Article  PubMed  CAS  Google Scholar 

  21. Kekule AS, Lauer U, Weiss L, Luber B, Hofschneider PH. Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway. Nature. 1993;361(6414):742–5.

    Article  PubMed  CAS  Google Scholar 

  22. Klein NP, Schneider RJ. Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras. Mol Cell Biol. 1997;17(11):6427–36.

    PubMed  CAS  Google Scholar 

  23. Lauer U, Weiss L, Hofschneider PH, Kekule AS. The hepatitis B virus pre-S/S(t) transactivator is generated by 3’ truncations within a defined region of the S gene. J Virol. 1992;66(9):5284–9.

    PubMed  CAS  Google Scholar 

  24. Martin-Lluesma S, Schaeffer C, Robert EI, van Breugel PC, Leupin O, Hantz O, et al. Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1. Hepatology. 2008;48(5):1467–76.

    Article  PubMed  CAS  Google Scholar 

  25. Matsuda Y, Ichida T. Impact of hepatitis B virus X protein on the DNA damage response during hepatocarcinogenesis. Med Mol Morphol. 2009;42(3):138–42.

    Article  PubMed  CAS  Google Scholar 

  26. Pan J, Duan LX, Sun BS, Feitelson MA. Hepatitis B virus X protein protects against anti-Fas-mediated apoptosis in human liver cells by inducing NF-kappa B. J Gen Virol. 2001;82(Pt 1):171–82.

    PubMed  CAS  Google Scholar 

  27. Park US, Park SK, Lee YI, Park JG, Lee YI. Hepatitis B virus-X protein upregulates the expression of p21waf1/cip1 and prolongs G1 → S transition via a p53-independent pathway in human hepatoma cells. Oncogene. 2000;19(30):3384–94.

    Article  PubMed  CAS  Google Scholar 

  28. Seeger C, Mason WS. Hepatitis B virus biology. Microbiol Mol Biol Rev. 2000;64(1):51–68.

    Article  PubMed  CAS  Google Scholar 

  29. Tang H, Oishi N, Kaneko S, Murakami S. Molecular functions and biological roles of hepatitis B virus x protein. Cancer Sci. 2006;97(10):977–83.

    Article  PubMed  CAS  Google Scholar 

  30. Peng Z, Zhang Y, Gu W, Wang Z, Li D, Zhang F, et al. Integration of the hepatitis B virus X fragment in hepatocellular carcinoma and its effects on the expression of multiple molecules: a key to the cell cycle and apoptosis. Int J Oncol. 2005;26(2):467–73.

    PubMed  CAS  Google Scholar 

  31. Su Q, Schroder CH, Hofmann WJ, Otto G, Pichlmayr R, Bannasch P. Expression of hepatitis B virus X protein in HBV-infected human livers and hepatocellular carcinomas. Hepatology. 1998;27(4):1109–20.

    Article  PubMed  CAS  Google Scholar 

  32. Hwang GY, Lin CY, Huang LM, Wang YH, Wang JC, Hsu CT, et al. Detection of the hepatitis B virus X protein (HBx) antigen and anti-HBx antibodies in cases of human hepatocellular carcinoma. J Clin Microbiol. 2003;41(12):5598–603.

    Article  PubMed  CAS  Google Scholar 

  33. Zhang H, Wu LY, Zhang S, Qiu LY, Li N, Zhang X, et al. Anti-hepatitis B virus X protein in sera is one of the markers of development of liver cirrhosis and liver cancer mediated by HBV. J Biomed Biotechnol. 2009;2009:289068.

    Google Scholar 

  34. Zhang Z, Torii N, Hu Z, Jacob J, Liang TJ. X-deficient woodchuck hepatitis virus mutants behave like attenuated viruses and induce protective immunity in vivo. J Clin Invest. 2001;108(10):1523–31.

    PubMed  CAS  Google Scholar 

  35. Zoulim F, Saputelli J, Seeger C. Woodchuck hepatitis virus X protein is required for viral infection in vivo. J Virol. 1994;68(3):2026–30.

    PubMed  CAS  Google Scholar 

  36. Kim CM, Koike K, Saito I, Miyamura T, Jay G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature. 1991;351(6324):317–20.

    Article  PubMed  CAS  Google Scholar 

  37. Kim SY, Lee PY, Shin HJ, Kim do H, Kang S, Moon HB, et al. Proteomic analysis of liver tissue from HBx-transgenic mice at early stages of hepatocarcinogenesis. Proteomics. 2009;9(22):5056–66.

    Article  PubMed  CAS  Google Scholar 

  38. Lee TH, Finegold MJ, Shen RF, DeMayo JL, Woo SL, Butel JS. Hepatitis B virus transactivator X protein is not tumorigenic in transgenic mice. J Virol. 1990;64(12):5939–47.

    PubMed  CAS  Google Scholar 

  39. Zhu H, Wang Y, Chen J, Cheng G, Xue J. Transgenic mice expressing hepatitis B virus X protein are more susceptible to carcinogen induced hepatocarcinogenesis. Exp Mol Pathol. 2004;76(1):44–50.

    Article  PubMed  CAS  Google Scholar 

  40. Terradillos O, Billet O, Renard CA, Levy R, Molina T, Briand P, et al. The hepatitis B virus X gene potentiates c-myc-induced liver oncogenesis in transgenic mice. Oncogene. 1997;14(4):395–404.

    Article  PubMed  CAS  Google Scholar 

  41. Singh M, Kumar V. Transgenic mouse models of hepatitis B virus-associated hepatocellular carcinoma. Rev Med Virol. 2003;13(4):243–53.

    Article  PubMed  CAS  Google Scholar 

  42. Wollersheim M, Debelka U, Hofschneider PH. A transactivating function encoded in the hepatitis B virus X gene is conserved in the integrated state. Oncogene. 1988;3(5):545–52.

    PubMed  CAS  Google Scholar 

  43. Paterlini P, Poussin K, Kew M, Franco D, Brechot C. Selective accumulation of the X transcript of hepatitis B virus in patients negative for hepatitis B surface antigen with hepatocellular carcinoma. Hepatology. 1995;21(2):313–21.

    PubMed  CAS  Google Scholar 

  44. Vitvitski-Trepo L, Kay A, Pichoud C, Chevallier P, de Dinechin S, Shamoon BM, et al. Early and frequent detection of HBxAg and/or anti-HBx in hepatitis B virus infection. Hepatology. 1990;12(6):1278–83.

    Article  PubMed  CAS  Google Scholar 

  45. Kremsdorf D, Soussan P, Paterlini-Brechot P, Brechot C. Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis. Oncogene. 2006;25(27):3823–33.

    Article  PubMed  CAS  Google Scholar 

  46. Nakatake H, Chisaka O, Yamamoto S, Matsubara K, Koshy R. Effect of X protein on transactivation of hepatitis B virus promoters and on viral replication. Virology. 1993;195(2):305–14.

    Article  PubMed  CAS  Google Scholar 

  47. Tang H, Delgermaa L, Huang F, Oishi N, Liu L, He F, et al. The transcriptional transactivation function of HBx protein is important for its augmentation role in hepatitis B virus replication. J Virol. 2005;79(9):5548–56.

    Article  PubMed  CAS  Google Scholar 

  48. Sung WK, Lu Y, Lee CW, Zhang D, Ronaghi M, Lee CG. Deregulated direct targets of the hepatitis B virus (HBV) protein, HBx, identified through chromatin immunoprecipitation and expression microarray profiling. J Biol Chem. 2009;284(33):21941–54.

    Article  PubMed  CAS  Google Scholar 

  49. Balsano C, Avantaggiati ML, Natoli G, De Marzio E, Will H, Perricaudet M, et al. Full-length and truncated versions of the hepatitis B virus (HBV) X protein (pX) transactivate the cmyc protooncogene at the transcriptional level. Biochem Biophys Res Commun. 1991;176(3):985–92.

    Article  PubMed  CAS  Google Scholar 

  50. Chirillo P, Falco M, Puri PL, Artini M, Balsano C, Levrero M, et al. Hepatitis B virus pX activates NF-kappa B-dependent transcription through a Raf-independent pathway. J Virol. 1996;70(1):641–6.

    PubMed  CAS  Google Scholar 

  51. Choi BH, Park GT, Rho HM. Interaction of hepatitis B viral X protein and CCAAT/ enhancer-binding protein alpha synergistically activates the hepatitis B viral enhancer II/pregenomic promoter. J Biol Chem. 1999;274(5):2858–65.

    Article  PubMed  CAS  Google Scholar 

  52. Kim HR, Lee SH, Jung G. The hepatitis B viral X protein activates NF-kappaB signaling pathway through the up-regulation of TBK1. FEBS Lett. 2010;584(3):525–30.

    Article  PubMed  CAS  Google Scholar 

  53. Tanaka Y, Kanai F, Ichimura T, Tateishi K, Asaoka Y, Guleng B, et al. The hepatitis B virus X protein enhances AP-1 activation through interaction with Jab1. Oncogene. 2006;25(4):633–42.

    PubMed  CAS  Google Scholar 

  54. Twu JS, Lai MY, Chen DS, Robinson WS. Activation of protooncogene c-jun by the X protein of hepatitis B virus. Virology. 1993;192(1):346–50.

    Article  PubMed  CAS  Google Scholar 

  55. Lee Y, Park US, Choi I, Yoon SK, Park YM, Lee YI. Human interleukin 6 gene is activated by hepatitis B virus-X protein in human hepatoma cells. Clin Cancer Res. 1998;4(7):1711–7.

    PubMed  CAS  Google Scholar 

  56. Amaro MJ, Bartolome J, Carreno V. Hepatitis B virus X protein transactivates the inducible nitric oxide synthase promoter. Hepatology. 1999;29(3):915–23.

    Article  PubMed  CAS  Google Scholar 

  57. Bui-Nguyen TM, Pakala SB, Sirigiri DR, Martin E, Murad F, Kumar R. Stimulation of inducible nitric oxide by hepatitis B virus transactivator protein-HBx requires MTA1 coregulator. J Biol Chem. 2010;285(10):6980–6.

    Google Scholar 

  58. Shin EC, Shin JS, Park JH, Kim H, Kim SJ. Expression of fas ligand in human hepatoma cell lines: role of hepatitis-B virus X (HBX) in induction of Fas ligand. Int J Cancer. 1999;82(4):587–91.

    Article  PubMed  CAS  Google Scholar 

  59. Yoo YG, Lee MO. Hepatitis B virus X protein induces expression of Fas ligand gene through enhancing transcriptional activity of early growth response factor. J Biol Chem. 2004;279(35):36242–9.

    Article  PubMed  CAS  Google Scholar 

  60. Lara-Pezzi E, Armesilla AL, Majano PL, Redondo JM, Lopez-Cabrera M. The hepatitis B virus X protein activates nuclear factor of activated T cells (NF-AT) by a cyclosporin A-sensitive pathway. EMBO J. 1998;17(23):7066–77.

    Article  PubMed  CAS  Google Scholar 

  61. Andrisani OM, Barnabas S. The transcriptional function of the hepatitis B virus X protein and its role in hepatocarcinogenesis (Review). Int J Oncol. 1999;15(2):373–9.

    PubMed  CAS  Google Scholar 

  62. Murata M, Matsuzaki K, Yoshida K, Sekimoto G, Tahashi Y, Mori S, et al. Hepatitis B virus X protein shifts human hepatic transforming growth factor (TGF)-beta signaling from tumor suppression to oncogenesis in early chronic hepatitis B. Hepatology. 2009;49(4):1203–17.

    Article  PubMed  CAS  Google Scholar 

  63. 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 USA. 1994;91(22):10350–4.

    Article  PubMed  CAS  Google Scholar 

  64. Cross JC, Wen P, Rutter WJ. Transactivation by hepatitis B virus X protein is promiscuous and dependent on mitogen-activated cellular serine/threonine kinases. Proc Natl Acad Sci USA. 1993;90(17):8078–82.

    Article  PubMed  CAS  Google Scholar 

  65. Lee YH, Yun Y. HBx protein of hepatitis B virus activates Jak1-STAT signaling. J Biol Chem. 1998;273(39):25510–5.

    Article  PubMed  CAS  Google Scholar 

  66. 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(8):4978–85.

    PubMed  CAS  Google Scholar 

  67. Um HR, Lim WC, Chae SY, Park S, Park JH, Cho H. Raf-1 and protein kinase B regulate cell survival through the activation of NF-kappaB in hepatitis B virus X-expressing cells. Virus Res. 2007;125(1):1–8.

    Article  PubMed  CAS  Google Scholar 

  68. Gearhart TL, Bouchard MJ. The hepatitis B virus X protein modulates hepatocyte proliferation pathways to stimulate viral replication. J Virol. 2010;84(6):2675–86.

    Article  PubMed  CAS  Google Scholar 

  69. Cha MY, Kim CM, Park YM, Ryu WS. Hepatitis B virus X protein is essential for the activation of Wnt/beta-catenin signaling in hepatoma cells. Hepatology. 2004;39(6):1683–93.

    Article  PubMed  CAS  Google Scholar 

  70. Ding Q, Xia W, Liu JC, Yang JY, Lee DF, Xia J, et al. Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell. 2005;19(2):159–70.

    Article  PubMed  CAS  Google Scholar 

  71. Li T, Robert EI, van Breugel PC, Strubin M, Zheng N. A promiscuous alpha-helical motif anchors viral hijackers and substrate receptors to the CUL4-DDB1 ubiquitin ligase machinery. Nat Struct Mol Biol. 2010;17(1):105–11.

    Article  PubMed  CAS  Google Scholar 

  72. Liu LP, Liang HF, Chen XP, Zhang WG, Yang SL, Xu T, et al. The role of NF-kappaB in hepatitis B virus X protein-mediated upregulation of VEGF and MMPs. Cancer Invest. 2010;28(5):443–51.

    Google Scholar 

  73. Lee SW, Lee YM, Bae SK, Murakami S, Yun Y, Kim KW. Human hepatitis B virus X protein is a possible mediator of hypoxia-induced angiogenesis in hepatocarcinogenesis. Biochem Biophys Res Commun. 2000;268(2):456–61.

    Article  PubMed  CAS  Google Scholar 

  74. Moon EJ, Jeong CH, Jeong JW, Kim KR, Yu DY, Murakami S, et al. Hepatitis B virus X protein induces angiogenesis by stabilizing hypoxia-inducible factor-1alpha. FASEB J. 2004;18(2):382–4.

    PubMed  CAS  Google Scholar 

  75. Holotnakova T, Tylkova L, Takacova M, Kopacek J, Petrik J, Pastorekova S, et al. Role of the HBx oncoprotein in carbonic anhydrase 9 induction. J Med Virol. 2010;82(1):32–40.

    Article  PubMed  CAS  Google Scholar 

  76. Feng H, Li X, Niu D, Chen WN. Protein profile in HBx transfected cells: a comparative iTRAQ-coupled 2D LC-MS/MS analysis. J Proteomics. 2009;73(8):1421–32.

    Google Scholar 

  77. Feng H, Zhang J, Li X, Chen WN. HBX-mediated migration of HBV-replicating HepG2 cells: insights on development of hepatocellular carcinoma. J Biomed Biotechnol. 2009;2009:930268.

    PubMed  Google Scholar 

  78. Li W, Miao X, Qi Z, Zeng W, Liang J, Liang Z. Hepatitis B virus X protein upregulates HSP90alpha expression via activation of c-Myc in human hepatocarcinoma cell line, HepG2. Virol J. 2010;7(1):45.

    Article  PubMed  CAS  Google Scholar 

  79. Xie B, Xing R, Chen P, Gou Y, Li S, Xiao J, et al. Down-regulation of c-Met expression inhibits human HCC cells growth and invasion by RNA interference. J Surg Res. 2010;162(2):231–8.

    Google Scholar 

  80. Bui-Nguyen TM, Pakala SB, Sirigiri RD, Xia W, Hung MC, Sarin SK, et al. NF-kappaB signaling mediates the induction of MTA1 by hepatitis B virus transactivator protein HBx. Oncogene. 2010;29(8):1179–89.

    Google Scholar 

  81. Lim W, Kwon SH, Cho H, Kim S, Lee S, Ryu WS, et al. HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression. J Mol Med. 2009.

  82. Chiu CM, Yeh SH, Chen PJ, Kuo TJ, Chang CJ, Chen PJ, et al. Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level. Proc Natl Acad Sci USA. 2007;104(8):2571–8.

    Article  PubMed  CAS  Google Scholar 

  83. Liu H, Shi W, Luan F, Xu S, Yang F, Sun W, et al. Hepatitis B virus X protein upregulates transcriptional activation of human telomerase reverse transcriptase. Virus Genes. 2010;40(2):174–82.

    Article  PubMed  CAS  Google Scholar 

  84. Feitelson MA, Zhu M, Duan LX, London WT. Hepatitis B x antigen and p53 are associated in vitro and in liver tissues from patients with primary hepatocellular carcinoma. Oncogene. 1993;8(5):1109–17.

    PubMed  CAS  Google Scholar 

  85. Lin Y, Nomura T, Yamashita T, Dorjsuren D, Tang H, Murakami S. The transactivation and p53-interacting functions of hepatitis B virus X protein are mutually interfering but distinct. Cancer Res. 1997;57(22):5137–42.

    PubMed  CAS  Google Scholar 

  86. Bergametti F, Prigent S, Luber B, Benoit A, Tiollais P, Sarasin A, et al. The proapoptotic effect of hepatitis B virus HBx protein correlates with its transactivation activity in stably transfected cell lines. Oncogene. 1999;18(18):2860–71.

    Article  PubMed  CAS  Google Scholar 

  87. Elmore LW, Hancock AR, Chang SF, Wang XW, Chang S, Callahan CP, et al. Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis. Proc Natl Acad Sci USA. 1997;94(26):14707–12.

    Article  PubMed  CAS  Google Scholar 

  88. Kim JY, Song EH, Lee HJ, Oh YK, Choi KH, Yu DY, et al. HBx-induced hepatic steatosis and apoptosis are regulated by TNFR1 and NF-jB-dependent pathway. J Mol Biol. 2010;397(4):917–31.

    Google Scholar 

  89. Ahn JY, Jung EY, Kwun HJ, Lee CW, Sung YC, Jang KL. Dual effects of hepatitis B virus X protein on the regulation of cell-cycle control depending on the status of cellular p53. J Gen Virol. 2002;83(Pt 11):2765–72.

    PubMed  CAS  Google Scholar 

  90. Chun E, Lee J, Cheong HS, Lee KY. Tumor eradication by hepatitis B virus X antigen-specific CD8+ T cells in xenografted nude mice. J Immunol. 2003;170(3):1183–90.

    PubMed  CAS  Google Scholar 

  91. Lee AT, Ren J, Wong ET, Ban KH, Lee LA, Lee CG. The hepatitis B virus X protein sensitizes HepG2 cells to UV light-induced DNA damage. J Biol Chem. 2005;280(39):33525–35.

    Article  PubMed  CAS  Google Scholar 

  92. 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(1-2):305–18.

    PubMed  CAS  Google Scholar 

  93. Zhang JL, Zhao WG, Wu KL, Wang K, Zhang X, Gu CF, et al. Human hepatitis B virus X protein promotes cell proliferation and inhibits cell apoptosis through interacting with a serine protease Hepsin. Arch Virol. 2005;150(4):721–41.

    Article  PubMed  CAS  Google Scholar 

  94. Zhang X, Dong N, Yin L, Cai N, Ma H, You J, et al. Hepatitis B virus X protein upregulates survivin expression in hepatoma tissues. J Med Virol. 2005;77(3):374–81.

    Article  PubMed  CAS  Google Scholar 

  95. Zhao J, Wu G, Bu F, Lu B, Liang A, Cao L, et al. Epigenetic silence of ankyrin-repeat-containing, SH3-domain-containing, and proline-rich-region- containing protein 1 (ASPP1) and ASPP2 genes promotes tumor growth in hepatitis B virus-positive hepatocellular carcinoma. Hepatology. 2010;51(1):142–53.

    PubMed  CAS  Google Scholar 

  96. Koike K, Moriya K, Yotsuyanagi H, Shintani Y, Fujie H, Tsutsumi T, et al. Compensatory apoptosis in preneoplastic liver of a transgenic mouse model for viral hepatocarcinogenesis. Cancer Lett. 1998;134(2):181–6.

    Article  PubMed  CAS  Google Scholar 

  97. Terradillos O, Pollicino T, Lecoeur H, Tripodi M, Gougeon ML, Tiollais P, et al. p53-independent apoptotic effects of the hepatitis B virus HBx protein in vivo and in vitro. Oncogene. 1998;17(16):2115–23.

    Article  PubMed  CAS  Google Scholar 

  98. Chirillo P, Pagano S, Natoli G, Puri PL, Burgio VL, Balsano C, et al. The hepatitis B virus X gene induces p53-mediated programmed cell death. Proc Natl Acad Sci USA. 1997;94(15):8162–7.

    Article  PubMed  CAS  Google Scholar 

  99. Lee MO, Choi YH, Shin EC, Kang HJ, Kim YM, Jeong SY, et al. Hepatitis B virus X protein induced expression of interleukin 18 (IL-18): a potential mechanism for liver injury caused by hepatitis B virus (HBV) infection. J Hepatol. 2002;37(3):380–6.

    Article  PubMed  CAS  Google Scholar 

  100. Liang X, Liu Y, Zhang Q, Gao L, Han L, Ma C, et al. Hepatitis B virus sensitizes hepatocytes to TRAIL-induced apoptosis through Bax. J Immunol. 2007;178(1):503–10.

    PubMed  CAS  Google Scholar 

  101. Miao J, Chen GG, Chun SY, Lai PP. Hepatitis B virus X protein induces apoptosis in hepatoma cells through inhibiting Bcl-xL expression. Cancer Lett. 2006;236(1):115–24.

    Article  PubMed  CAS  Google Scholar 

  102. Kalra N, Kumar V. c-Fos is a mediator of the c-myc-induced apoptotic signaling in serum-deprived hepatoma cells via the p38 mitogen-activated protein kinase pathway. J Biol Chem. 2004;279(24):25313–9.

    Article  PubMed  CAS  Google Scholar 

  103. Bergametti F, Sitterlin D, Transy C. Turnover of hepatitis B virus X protein is regulated by damaged DNA-binding complex. J Virol. 2002;76(13):6495–501.

    Article  PubMed  CAS  Google Scholar 

  104. Sitterlin D, Bergametti F, Transy C. UVDDB p127-binding modulates activities and intracellular distribution of hepatitis B virus X protein. Oncogene. 2000;19(38):4417–26.

    Article  PubMed  CAS  Google Scholar 

  105. Cheng P, Li Y, Yang L, Wen Y, Shi W, Mao Y, et al. Hepatitis B virus X protein (HBx) induces G2/M arrest and apoptosis through sustained activation of cyclin B1-CDK1 kinase. Oncol Rep. 2009;22(5):1101–7.

    PubMed  CAS  Google Scholar 

  106. Assrir N, Soussan P, Kremsdorf D, Rossignol JM. Role of the hepatitis B virus proteins in pro- and anti-apoptotic processes. Front Biosci. 2010;15:12–24.

    Article  PubMed  CAS  Google Scholar 

  107. Lau JY, Xie X, Lai MM, Wu PC. Apoptosis and viral hepatitis. Semin Liver Dis. 1998;18(2):169–76.

    Article  PubMed  CAS  Google Scholar 

  108. Lee YI, Hwang JM, Im JH, Lee YI, Kim NS, Kim DG, et al. Human hepatitis B virus-X protein alters mitochondrial function and physiology in human liver cells. J Biol Chem. 2004;279(15):15460–71.

    Article  PubMed  CAS  Google Scholar 

  109. Takada S, Shirakata Y, Kaneniwa N, Koike K, Koike K. Association of hepatitis B virus X protein with mitochondria causes mitochondrial aggregation at the nuclear periphery, leading to cell death. Oncogene. 1999;18(50):6965–73.

    Article  PubMed  CAS  Google Scholar 

  110. Tan C, Guo H, Zheng M, Chen Y, Huang W. Involvement of mitochondrial permeability transition in hepatitis B virus replication. Virus Res. 2009;145(2):307–11.

    Article  PubMed  CAS  Google Scholar 

  111. Tanaka Y, Kanai F, Kawakami T, Tateishi K, Ijichi H, Kawabe T, et al. Interaction of the hepatitis B virus X protein (HBx) with heat shock protein 60 enhances HBx-mediated apoptosis. Biochem Biophys Res Commun. 2004;318(2):461–9.

    Article  PubMed  CAS  Google Scholar 

  112. Zhang SM, Sun DC, Lou S, Bo XC, Lu Z, Qian XH, et al. HBx protein of hepatitis B virus (HBV) can form complex with mitochondrial HSP60 and HSP70. Arch Virol. 2005;150(8):1579–90.

    Article  PubMed  CAS  Google Scholar 

  113. Rahmani Z, Huh KW, Lasher R, Siddiqui A. Hepatitis B virus X protein colocalizes to mitochondria with a human voltage-dependent anion channel, HVDAC3, and alters its transmembrane potential. J Virol. 2000;74(6):2840–6.

    Article  PubMed  CAS  Google Scholar 

  114. Feitelson MA, Lee J. Hepatitis B virus integration, fragile sites, and hepatocarcinogenesis. Cancer Lett. 2007;252(2):157–70.

    Article  PubMed  CAS  Google Scholar 

  115. Becker SA, Lee TH, Butel JS, Slagle BL. Hepatitis B virus X protein interferes with cellular DNA repair. J Virol. 1998;72(1):266–72.

    PubMed  CAS  Google Scholar 

  116. Jia L, Wang XW, Harris CC. Hepatitis B virus X protein inhibits nucleotide excision repair. Int J Cancer. 1999;80(6):875–9.

    Article  PubMed  CAS  Google Scholar 

  117. Wang XW, Forrester K, Yeh H, Feitelson MA, Gu JR, Harris CC. Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc Natl Acad Sci USA. 1994;91(6):2230–4.

    Google Scholar 

  118. Groisman IJ, Koshy R, Henkler F, Groopman JD, Alaoui-Jamali MA. Downregulation of DNA excision repair by the hepatitis B virus-x protein occurs in p53-proficient and p53-deficient cells. Carcinogenesis. 1999;20(3):479–83.

    Article  PubMed  CAS  Google Scholar 

  119. Cheng B, Zheng Y, Guo X, Wang Y, Liu C. Hepatitis B viral X protein alters the biological features and expressions of DNA repair enzymes in LO2 cells. Liver Int. 2010;30(2):319–26.

    Google Scholar 

  120. Jung JK, Park SH, Jang KL. Hepatitis B virus X protein overcomes the growth-inhibitory potential of retinoic acid by downregulating retinoic acid receptor-beta2 expression via DNA methylation. J Gen Virol. 2009;91(Pt 2):493–500.

    PubMed  Google Scholar 

  121. 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(44):6617–25.

    Article  PubMed  CAS  Google Scholar 

  122. Zhu YZ, Zhu R, Fan J, Pan Q, Li H, Chen Q, et al. Hepatitis B virus X protein induces hypermethylation of p16(INK4A) promoter via DNA methyltransferases in the early stage of HBV-associated hepatocarcinogenesis. J Viral Hepat. 2009;17(2):98–107.

    PubMed  Google Scholar 

  123. Kim YJ, Jung JK, Lee SY, Jang KL. Hepatitis B virus X protein overcomes stress-induced premature senescence by repressing p16(INK4a) expression via DNA methylation. Cancer Lett. 2010;288(2):226–35.

    Article  PubMed  CAS  Google Scholar 

  124. Wang Y, Lu Y, Toh ST, Sung W, Tan P, Chow P, et al. Lethal-7 is down-regulated by the hepatitis B virus x protein and targets signal transducer and activator of transcription 3. J Hepatol. 2010;53(1):57–66.

    Google Scholar 

  125. Chen GG, Li MY, Ho RL, Chak EC, Lau WY, Lai PB. Identification of hepatitis B virus X gene mutation in Hong Kong patients with hepatocellular carcinoma. J Clin Virol. 2005;34(1):7–12.

    Article  PubMed  CAS  Google Scholar 

  126. Guo X, Jin Y, Qian G, Tu H. Sequential accumulation of the mutations in core promoter of hepatitis B virus is associated with the development of hepatocellular carcinoma in Qidong, China. J Hepatol. 2008;49(5):718–25.

    Article  PubMed  CAS  Google Scholar 

  127. Iavarone M, Trabut JB, Delpuech O, Carnot F, Colombo M, Kremsdorf D, et al. Characterisation of hepatitis B virus X protein mutants in tumour and non-tumour liver cells using laser capture microdissection. J Hepatol. 2003;39(2):253–61.

    Article  PubMed  CAS  Google Scholar 

  128. Kim JK, Chang HY, Lee JM, Baatarkhuu O, Yoon YJ, Park JY, et al. Specific mutations in the enhancer II/core promoter/precore regions of hepatitis B virus subgenotype C2 in Korean patients with hepatocellular carcinoma. J Med Virol. 2009;81(6):1002–8.

    Article  PubMed  CAS  Google Scholar 

  129. Lin X, Xu X, Huang QL, Liu YQ, Zheng DL, Chen WN, et al. Biological impacts of “hot-spot” mutations of hepatitis B virus X proteins are genotype B and C differentiated. World J Gastroenterol. 2005;11(30):4703–8.

    PubMed  CAS  Google Scholar 

  130. Sirma H, Giannini C, Poussin K, Paterlini P, Kremsdorf D, Brechot C. Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx. Oncogene. 1999;18(34):4848–59.

    Article  PubMed  CAS  Google Scholar 

  131. Tu H, Bonura C, Giannini C, Mouly H, Soussan P, Kew M, et al. Biological impact of natural COOH-terminal deletions of hepatitis B virus X protein in hepatocellular carcinoma tissues. Cancer Res. 2001;61(21):7803–10.

    PubMed  CAS  Google Scholar 

  132. Yeh CT, Shen CH, Tai DI, Chu CM, Liaw YF. Identification and characterization of a prevalent hepatitis B virus X protein mutant in Taiwanese patients with hepatocellular carcinoma. Oncogene. 2000;19(46):5213–20.

    Article  PubMed  CAS  Google Scholar 

  133. Hsia CC, Nakashima Y, Tabor E. Deletion mutants of the hepatitis B virus X gene in human hepatocellular carcinoma. Biochem Biophys Res Commun. 1997;241(3):726–9.

    Article  PubMed  CAS  Google Scholar 

  134. Poussin K, Dienes H, Sirma H, Urban S, Beaugrand M, Franco D, et al. Expression of mutated hepatitis B virus X genes in human hepatocellular carcinomas. Int J Cancer. 1999;80(4):497–505.

    Article  PubMed  CAS  Google Scholar 

  135. Ma NF, Lau SH, Hu L, Xie D, Wu J, Yang J, et al. COOH-terminal truncated HBV X protein plays key role in hepatocarcinogenesis. Clin Cancer Res. 2008;14(16):5061–8.

    Article  PubMed  CAS  Google Scholar 

  136. Kumar V, Jayasuryan N, Kumar R. A truncated mutant (residues 58–140) of the hepatitis B virus X protein retains transactivation function. Proc Natl Acad Sci USA. 1996;93(11):5647–52.

    Article  PubMed  CAS  Google Scholar 

  137. Qadri I, Maguire HF, Siddiqui A. Hepatitis B virus transactivator protein X interacts with the TATA-binding protein. Proc Natl Acad Sci USA. 1995;92(4):1003–7.

    Article  PubMed  CAS  Google Scholar 

  138. Cheong JH, Yi M, Lin Y, Murakami S. Human RPB5, a subunit shared by eukaryotic nuclear RNA polymerases, binds human hepatitis B virus X protein and may play a role in X transactivation. EMBO J. 1995;14(1):143–50.

    PubMed  CAS  Google Scholar 

  139. Takada S, Kido H, Fukutomi A, Mori T, Koike K. Interaction of hepatitis B virus X protein with a serine protease, tryptase TL2 as an inhibitor. Oncogene. 1994;9(2):341–8.

    PubMed  CAS  Google Scholar 

  140. Hsia CC, Yuwen H, Tabor E. Hot-spot mutations in hepatitis B virus X gene in hepatocellular carcinoma. Lancet. 1996;348(9027):625–6.

    Article  PubMed  CAS  Google Scholar 

  141. Takahashi K, Akahane Y, Hino K, Ohta Y, Mishiro S. Hepatitis B virus genomic sequence in the circulation of hepatocellular carcinoma patients: comparative analysis of 40 full-length isolates. Arch Virol. 1998;143(12):2313–26.

    Article  PubMed  CAS  Google Scholar 

  142. Wang Q, Zhang W, Liu Q, Zhang X, Lv N, Ye L, et al. A mutant of hepatitis B virus X protein (HBxDelta127) promotes cell growth through a positive feedback loop involving 5-lipoxygenase and fatty acid synthase. Neoplasia. 2010;12(2):103–15.

    PubMed  Google Scholar 

  143. Wang Q, Zhang WY, Ye LH, Zhang XD. A mutant of HBx (HBxDelta127) promotes hepatoma cell growth via sterol regulatory element binding protein 1c involving 5-lipoxygenase. Acta Pharmacol Sin. 2010;31(3):367–74.

    Google Scholar 

  144. Jiang W, Wang XW, Unger T, Forgues M, Kim JW, Hussain SP, et al. Cooperation of tumor-derived HBx mutants and p53-249(ser) mutant in regulating cell proliferation, anchorage-independent growth and aneuploidy in a telomerase-immortalized normal human hepatocyte-derived cell line. Int J Cancer. 2010;127(5):1011–20.

    Google Scholar 

  145. Belloni L, Pollicino T, De Nicola F, Guerrieri F, Raffa G, Fanciulli M, et al. Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function. Proc Natl Acad Sci USA. 2009;106(47):19975–9.

    PubMed  CAS  Google Scholar 

  146. Cheng AS, Wong N, Tse AM, Chan KY, Chan KK, Sung JJ, et al. RNA interference targeting HBx suppresses tumor growth and enhances cisplatin chemosensitivity in human hepatocellular carcinoma. Cancer Lett. 2007;253(1):43–52.

    Article  PubMed  CAS  Google Scholar 

  147. He Y, Sun HQ, He XE, Wang WL, Lei JH. Knockdown of HBx by RNAi inhibits proliferation and enhances chemotherapy-induced apoptosis in hepatocellular carcinoma cells. Med Oncol. 2010;27(4):1227–33.

    Google Scholar 

  148. Chan DW, Ng IO. Knock-down of hepatitis B virus X protein reduces the tumorigenicity of hepatocellular carcinoma cells. J Pathol. 2006;208(3):372–80.

    Article  PubMed  CAS  Google Scholar 

  149. Xian L, Zhao J, Wang J, Fang Z, Peng B, Wang W, et al. p53 Promotes proteasome-dependent degradation of oncogenic protein HBx by transcription of MDM2. Mol Biol Rep. 2009.

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sue-Ann Ng.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ng, SA., Lee, C. Hepatitis B virus X gene and hepatocarcinogenesis. J Gastroenterol 46, 974–990 (2011). https://doi.org/10.1007/s00535-011-0415-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-011-0415-9

Keywords

Navigation