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HBV Signaling

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Signaling Pathways in Liver Diseases

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Abstract

Infection with hepatitis B virus (HBV) continues to be a major health problem with about 400 million people chronically infected worldwide who are at high risk of developing liver cirrhosis and hepatocellular carcinoma (HCC) [1].

HBV is a member of the Hepadnaviridae family which includes small enveloped DNA viruses infecting primates, rodents, and birds [2,3]. One common characteristic of these viruses is their high species and cell-type specificity, as well as a unique genomic organization and replication mechanism. The genome of all hepadnaviruses is extremely compact consisting of four overlapping open reading frames (ORF). The S, Core and Pol ORFs encode viral proteins that are essential structural components of viral replication and assembly (envelope proteins (SHBs, MHBs and LHBs), core (HBc) and reverse transcriptase (RT)/polymerase (Pol)). The HBeAg, which is generated by the intracellular processing of the preC/Core protein at the endoplasmic reticulum (ER) levels as well as by intracellular and extracellular proteolysis of free HBc proteins, is thought to play an important role in HBV pathogenesis by influencing the host immune system . The X ORF encodes for the regulatory X protein (hepatitis B virus X protein (HBx)) which is an essential factor for viral replication and it is considered to be one of the most important determinants of HBV-induced hepatocarcinogenesis [4]. Whereas many aspects of viral replication have been elucidated, the initial phases of hepadnaviral infection (attachment of mature virions onto host cell membranes and viral entry) are still less understood, and the search for putative cellular receptors and coreceptors is still very active. An additional important feature of hepadnaviruses replication is the relative low fidelity of the ­enzimatic machinery that leads to high genomic heterogeneity and variability [2,3].

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References

  1. Shepard CW, Simard EP, Finelli L, Fiore AE, Bell BP. Hepatitis B virus infection: epidemiology and vaccination. Epidemiol Rev. 2006;28:112–125

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Seeger C, Mason WS, Zoulim F. Hepadnaviruses. In: Knipe DM, Howley PM, editors. Fields virology. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 2977–3029

    Google Scholar 

  4. Tang H, Oishi N, Kaneko S, Murakami S. Molecular functions and biological roles of hepatitis B virus x protein. Cancer Sci. 2006;97:977–983

    Article  PubMed  CAS  Google Scholar 

  5. Raimondo G, Pollicino T, Cacciola I, Squadrito G. Occult hepatitis B virus infection. J Hepatol. 2007;46:160–170

    Article  PubMed  Google Scholar 

  6. Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M, et al Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol. 2008;49:652–657

    Article  PubMed  Google Scholar 

  7. Tuttleman JS, Pourcel C, Summers J. Formation of the pool of covalently closed circular viral DNA in hepadnavirus-infected cells. Cell. 1986;47:451–460

    Article  PubMed  CAS  Google Scholar 

  8. Hirsch RC, Lavine JE, Chang LJ, Varmus HE, Ganem D. Polymerase gene products of hepatitis B viruses are required for genomic RNA packaging as well as for reverse transcription. Nature. 1990;344:552–555

    Article  PubMed  CAS  Google Scholar 

  9. Bartenschlager R, Schaller H. Hepadnaviral assembly is initiated by polymerase binding to the encapsidation signal in the viral RNA genome. EMBO J. 1992;11:3413–3420

    PubMed  CAS  Google Scholar 

  10. Gerlich WH, Robinson WS. Hepatitis B virus contains protein attached to the 50 terminus of its complete DNA strand. Cell. 1980;21:801–809.

    Article  PubMed  CAS  Google Scholar 

  11. Wang GH, Seeger C. The reverse transcriptase of hepatitis B virus acts as a protein primer for viral DNA synthesis. Cell. 1992;71:663–670

    Article  PubMed  CAS  Google Scholar 

  12. Weber M, Bronsema V, Bartos H, Bosserhoff A, Bartenschlager R, Schaller H. Hepadnavirus P protein utilizes a tyrosine residue in the TP domain to prime reverse transcription. J Virol. 1994;68:2994–2999

    PubMed  CAS  Google Scholar 

  13. Zoulim F, Seeger C. Reverse transcription in hepatitis B viruses is primed by a tyrosine residue of the polymerase.J Virol. 1994;68:6–13

    PubMed  CAS  Google Scholar 

  14. Wu TT, Coates L, Aldrich CE, Summers J, Mason WS. In hepatocytes infected with duck hepatitis B virus, the template for viral RNA synthesis is amplified by an intracellular pathway. Virology. 1990;175:255–261

    Article  PubMed  CAS  Google Scholar 

  15. Hu J, Toft D, Anselmo D, Wang X. In vitro reconstitution of functional hepadnavirus reverse transcriptase with cellular chaperone proteins. J Virol. 2002;76:269–279

    Article  PubMed  CAS  Google Scholar 

  16. Hu J, Flores D, Toft D, Wang X, Nguyen D. Requirement of heat shock protein 90 for human hepatitis B virus reverse transcriptase function. J Virol. 2004;78:13122–13131

    Article  PubMed  CAS  Google Scholar 

  17. Schlicht HJ, Bartenschlager R, Schaller H. The duck hepatitis B virus core protein contains a highly phosphorylated C terminus that is essential for replication but not for RNA packaging. J Virol. 1989;63:2995–3000

    PubMed  CAS  Google Scholar 

  18. Nassal M. The arginine-rich domain of the hepatitis B virus core protein is required for pregenome encapsidation and productive viral positive-strand DNA synthesis but not for virus assembly. J Virol. 1992;66:4107–4116

    PubMed  CAS  Google Scholar 

  19. Yu M, Summers J. Multiple functions of capsid protein phosphorylation in duck hepatitis B virus replication.J Virol. 1994;68:4341–4348

    PubMed  CAS  Google Scholar 

  20. Perlman DH, Berg EA, O’Connor PB, Costello CE. Hu J Reverse transcription-associated dephosphorylation of hepadnavirus nucleocapsids. Proc Natl Acad Sci USA. 2005;102:9020–9025

    Article  PubMed  CAS  Google Scholar 

  21. Pugh J, Zweidler A, Summers J. Characterization of the major duck hepatitis B virus core particle protein. J Virol. 1989;63:1371–1376

    PubMed  CAS  Google Scholar 

  22. Melegari M, Wolf SK, Schneider RJ. Hepatitis B virusDNAreplication is coordinated by core protein serine phosphorylation and HBx expression. J Virol. 2005;79:9810–9820

    Article  PubMed  CAS  Google Scholar 

  23. Yeh CT, Ou JH. Phosphorylation of hepatitis B virus precore and core proteins. J Virol. 1991;65:2327–2331

    PubMed  CAS  Google Scholar 

  24. Basagoudanavar SH, Perlman DH, Hu J. Regulation of hepadnavirus reverse transcription by dynamic nucleocapsid phosphorylation. J Virol. 2007;81:1641–1649

    Article  PubMed  CAS  Google Scholar 

  25. Albin C, Robinson WS. Protein kinase activity in hepatitis B virus. J Virol. 1980;34:297–302

    PubMed  CAS  Google Scholar 

  26. Barrasa MI, Guo JT, Saputelli J, Mason WS, Seeger C. Does a cdc2 kinase-like recognition motif on the core protein of hepadnaviruses regulate assembly and disintegration of capsids? J Virol. 2001;75:2024–2028

    Article  PubMed  CAS  Google Scholar 

  27. Kau JH, Ting LP. Phosphorylation of the core protein of hepatitis B virus by a 46-kilodalton serine kinase. J Virol. 1998;72:3796–3803

    PubMed  CAS  Google Scholar 

  28. Daub H, Blencke S, Habenberger P, Kurtenbach A, Dennenmoser J, Wissing J, et al Identification of SRPK1 and SRPK2 as the major cellular protein kinases phosphorylating hepatitis B virus core protein. J Virol. 2002;76:8124–8137

    Article  PubMed  CAS  Google Scholar 

  29. Zhang YY, Zhang BH, Theele D, Litwin S, Toll E, Summers J. Single-cell analysis of covalently closed circular DNA copy numbers in a hepadnavirus-infected liver. Proc Natl Acad Sci USA. 2003;100:12372–12377

    Article  PubMed  CAS  Google Scholar 

  30. Locarnini S, Mason WS. Cellular and virological mechanisms of HBV drug resistance. J Hepatol. 2006;44:422–431

    Article  PubMed  CAS  Google Scholar 

  31. Newbold JE, Xin H, Tencza M, Sherman G, Dean J, Bowden S, et al The covalently closed duplex form of the hepadnavirus genome exists in situ as a heterogeneous population of viral minichromosomes. J Virol. 1995;69: 3350–3357

    PubMed  CAS  Google Scholar 

  32. Pollicino T, Belloni L, Raffa G, Pediconi N, Squadrito G, Raimondo G, et al Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones. Gastroenterology. 2006;130: 823–837

    Article  PubMed  CAS  Google Scholar 

  33. Guidotti LG, Matzke B, Schaller H, Chisari FV. High-level hepatitis B virus replication in transgenic mice. J Virol. 1995;69:6158–6169

    PubMed  CAS  Google Scholar 

  34. Belloni L, Pollicino T, Cimino L, Raffa G, Raimondo G, Levrero M. HBX binds in vivo on the HBV minichromosome, modifies the epigenetic regulation of ccc-DNA function and potentiates HBV replication. J Hepatol. 2008;48 (suppl 2):S25.

    Article  Google Scholar 

  35. Levrero M, Pollicino T, Petersen J, Belloni L, Raimondo G, Dandri M. Control of cccDNA function in hepatitis B virus infection. J Hepatol 2009;51:581–92.

    Google Scholar 

  36. Chen HS, Kaneko S, Girones R, Anderson RW, Hornbuckle WE, Tennant BC, et al The woodchuck hepatitis virus X gene is important for establishment of virus infection in woodchucks. J Virol. 1993;67:1218–1226

    PubMed  CAS  Google Scholar 

  37. Zoulim F, Saputelli J, Seeger C. Woodchuck hepatitis virus X protein is required for viral infection in vivo. J Virol. 1994;68:2026–2030

    PubMed  CAS  Google Scholar 

  38. 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;81:2656–2662

    Article  PubMed  CAS  Google Scholar 

  39. Bouchard MJ, Schneider RJ. The enigmatic X gene of hepatitis B virus. J Virol. 2004;78:12725–12734

    Article  PubMed  CAS  Google Scholar 

  40. Doria M, Klein N, Lucito R, Schneider RJ. The hepatitis B virus HBx protein is a dual specificity cytoplasmic activator of Ras and nuclear activator of transcription factors. EMBO J. 1995;14:4747–4757

    PubMed  CAS  Google Scholar 

  41. Werle-Lapostolle B, Bowden S, Locarnini S, Wursthorn K, Petersen J, Lau G, et al Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology. 2004;126:1750–1758

    Article  PubMed  CAS  Google Scholar 

  42. 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;14:143–150.

    PubMed  CAS  Google Scholar 

  43. Seto E, Mitchell PJ, Yen TS. Transactivation by the hepatitis B virus X protein depends on AP-2 and other transcription factors. Nature. 1990;344:72–74

    Article  PubMed  CAS  Google Scholar 

  44. Maguire HF, Hoeffler JP, Siddiqui A. HBVXprotein alters theDNAbinding specificity of CREB and ATF-2 byprotein-protein interactions. Science. 1991;252:842–844

    Article  PubMed  CAS  Google Scholar 

  45. Cougot D, Wu Y, Cairo S, Caramel J, Renard CA, Lévy L, 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: 4277–4287

    Article  PubMed  CAS  Google Scholar 

  46. 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;70:641–646

    PubMed  CAS  Google Scholar 

  47. Weil R, Sirma H, Giannini C, Kremsdorf D, Bessia C, Dargemont C, et al Direct association and nuclear import of the hepatitis B virus X protein with the NF-kappaB inhibitor IkappaBalpha. Mol Cell Biol. 1999;9:6345–6354

    Google Scholar 

  48. 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: 4978–4985

    PubMed  CAS  Google Scholar 

  49. Bouchard MJ, Wang LH, Schneider RJ. Calcium signaling by HBx protein in hepatitis B virus DNA replication. Science. 2001;294:2376–2378

    Article  PubMed  CAS  Google Scholar 

  50. Chami M, Ferrari D, Nicotera P, Paterlini-Brechot P, Rizzuto P. Caspase-dependent alterations of Ca2+ signaling in the induction of apoptosis by hepatitis B virus X protein. J Biol Chem. 2003;278:31745–31755

    Article  PubMed  CAS  Google Scholar 

  51. Bouchard MJ, Puro RJ, Wang L, Schneider RJ. Activation and inhibition of cellular calcium and tyrosine kinase signaling pathways identify targets of the HBx protein involved in hepatitis B virus replication. J Virol. 2003;77:7713–7719

    Article  PubMed  CAS  Google Scholar 

  52. Bouchard MJ, Wang L, Schneider LJ. Activation of focal adhesion kinase by hepatitis B virus HBx protein: multiple functions in viral replication. J Virol. 2006;80:4406–4414

    Article  PubMed  CAS  Google Scholar 

  53. Ganem D, Prince AM. Hepatitis B virus infection–natural history and clinical consequences. N Engl J Med. 2004;350:1118–1129

    Article  PubMed  CAS  Google Scholar 

  54. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol. 2005;5:215–229

    Article  PubMed  CAS  Google Scholar 

  55. Bruss V. Revisiting the cytopathic effect of hepatitis B virus infection. Hepatology. 2002;36:1327–1329

    PubMed  CAS  Google Scholar 

  56. Foo NC, Ahn BY, Ma X, Hyun W, Yen TS. Cellular vacuolization and apoptosis induced by hepatitis B virus large surface protein. Hepatology. 2002;36:1400–1407

    PubMed  CAS  Google Scholar 

  57. Chisari FV, Klopchin K, Moriyama T. Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell. 1989;59:1145–1156

    Article  PubMed  CAS  Google Scholar 

  58. Warner N, Locarnini S. The antiviral drug selected hepatitis B virus rtA181T/sW172* mutant has a dominant negative secretion defect and alters the typical profile of viral rebound. Hepatology. 2008;48:88–98

    Article  PubMed  CAS  Google Scholar 

  59. Lenhoff RJ, Summers J. Construction of avian hepadnavirus variants with enhanced replication and cytopathicity in primary hepatocytes. J Virol. 1994;68:5706–5713

    PubMed  CAS  Google Scholar 

  60. Lenhoff RJ, Luscombe CA, Summers J. Acute liver injury following infection with a cytopathic strain of duck hepatitis B virus. Hepatology. 1999;29:563–571

    Article  PubMed  CAS  Google Scholar 

  61. Baumert TF, Yang C, Schurmann P, Kock J, Ziegler C, Grullich C, et al Hepatitis B virus mutations associated with fulminant hepatitis induce apoptosis in primary Tupaia hepatocytes. Hepatology. 2005;41:247–256

    Article  PubMed  CAS  Google Scholar 

  62. Su F, Theodosis CN, Schneider RJ. Role of NF-kappaB and myc proteins in apoptosis induced by hepatitis B virus HBx protein. J Virol. 2001;75:215–225

    Article  PubMed  CAS  Google Scholar 

  63. Kim KH, Seong BL. Pro-apoptotic function of HBV X protein is mediated by interaction with c-FLIP and enhancement of death-inducing signal. EMBO J. 2003;22:2104–2116

    Article  PubMed  CAS  Google Scholar 

  64. 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;94:8162–8167

    Article  PubMed  CAS  Google Scholar 

  65. Sirma H, Giannini C, Poussin K, Paterlini P, Kremsdorf D, Bréchot C. Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx. Oncogene. 1999;18:4848–4859

    Article  PubMed  CAS  Google Scholar 

  66. Wang XW, Gibson MK, Vermeulen W, Yeh H, Forrester K, Stürzbecher HW, et al Abrogation of p53-induced apoptosis by the hepatitis B virus X gene. Cancer Res. 1995;55: 6012–6016

    PubMed  CAS  Google Scholar 

  67. Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 1995;3:673–682

    Article  PubMed  CAS  Google Scholar 

  68. Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science. 1997;277:815–818

    Article  PubMed  CAS  Google Scholar 

  69. Liang X, Liu Y, Zhang Q, Gao L, Han L, Ma C, et al Hepatitis B virus sensitizes hepatocyte to TRAIL-induced apoptosis through Bax. J Immunol. 2007;178:503–510

    PubMed  CAS  Google Scholar 

  70. Liu YG, Liu SX, Liang XH, Zhang Q, Gao LF, Han LH,et al Blockade of TRAIL pathway ameliorates HBV-induced hepatocyte apoptosis in an acute hepatitis model. Bioche Biophys Res Commun. 2007;352:329–334

    Article  CAS  Google Scholar 

  71. Liang X, Du J, Liu Y, Cui M, Ma C, Han L, et al The hepatitis B virus protein MHBs(t) sensitizes hepatoma cells to TRAIL-induced apoptosis through ERK2. Apoptosis. 2007;12:1827–1836

    Article  PubMed  CAS  Google Scholar 

  72. Du J, Liang X, Liu Y, Qu Z, Gao L, Han L, et al Hepatitis B virus core protein inhibits TRAIL-induced apoptosis of hepatocytes by blocking DR5 expression. Cell Death Differ. 2009;16:219–229

    Article  PubMed  CAS  Google Scholar 

  73. Kwon JA, Rho HM. Transcriptional repression of the human p53 gene by hepatitis B viral core protein (HBc) in human liver cells. Biol Chem. 2003;384:203–212

    Article  PubMed  CAS  Google Scholar 

  74. Kim JH, Kang S, Kim J, Ahn BY. Hepatitis B virus core protein stimulates the proteasome mediated degradation of viral x protein. J Virol. 2003;77:7166–7173

    Article  PubMed  CAS  Google Scholar 

  75. Whitten TM, Quets AT, Schloemer RH. Dentification of the hepatitis B virus factor that inhibits expression of the b interferon gene. J virol. 1991;65:4699–4704

    PubMed  CAS  Google Scholar 

  76. Leandro G, Mangia A, Hui J, Fabris P, Rubbia-Brandt L, Colloredo G, et al; HCV Meta-Analysis (on) Individual Patients’ Data Study Group (2006) Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology 130:1636–1642

    Google Scholar 

  77. Tsochatzis E, Papatheodoridis GV, Manesis EK, Chrysanthos N, Kafiri G, Archimandritis AJ. Hepatic steatosis in chronic hepatitis B develops due to host metabolic factors: a comparative approach with genotype 1 chronic hepatitis C. Dig Liver Dis. 2007;39:936–942

    Article  PubMed  CAS  Google Scholar 

  78. Gordon A, McLean CA, Pedersen JS, Bailey MJ, Roberts SK. Hepatic steatosis in chronic hepatitis B and C: predictors, distribution and effect on fibrosis. J Hepatol. 2005;43:38–44

    Article  PubMed  CAS  Google Scholar 

  79. Su AI, Pezacki JP, Wodicka L, Brideau AD, Supekova L, Thimme R, et al Genomic analysis of the host response to hepatitis C virus infection. Proc Natl Acad Sci U S A. 2002;26:15669–15674

    Article  CAS  Google Scholar 

  80. Moriishi K, Mochizuki R, Moriya K, Miyamoto H, Mori Y, Abe T, et al Critical role of PA28gamma in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis. Proc Natl Acad Sci U S A. 2007;104:1661–1666

    Article  PubMed  CAS  Google Scholar 

  81. Hajjou M, Norel R, Carver R, Marion P, Cullen J, Rogler LE, et al cDNA microarray analysis of HBV transgenic mouse liver identifies genes in lipid biosynthetic and growth control pathways affected by HBV. J Med Virol. 2005;77:57–65

    Article  PubMed  CAS  Google Scholar 

  82. Kim KH, Shin HJ, Kim K, Choi HM, Rhee SH, Moon HB, et al Hepatitis B virus X protein induces hepatic steatosis via transcriptional activation of SREBP1 and PPARgamma. Gastroenterology. 2007;132:1955–1967

    Article  PubMed  CAS  Google Scholar 

  83. Na TY, Shin YK, Roh KJ, Kang SA, Hong I, Oh SJ, et al Liver X receptor mediates hepatitis B virus X protein-induced lipogenesis in hepatitis B virus-associated hepatocellular carcinoma. Hepatology. 2009;4:1122–1131

    Article  Google Scholar 

  84. Fattovich G, Stroffolini T, Zagni I, et al Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35–S50

    Article  Google Scholar 

  85. El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology. 2004;127:27–35

    Article  Google Scholar 

  86. Taylor-Robinson SD, Foster GR, Arora S, et al Increase in primary liver cancer in the UK, 1979–1994. Lancet. 1997;350:1142–1143

    Article  PubMed  CAS  Google Scholar 

  87. Moradpour D, Blum HE. Pathogenesis of hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 2005;17:477–483

    Article  PubMed  Google Scholar 

  88. Levrero M. Viral hepatitis and liver cancer: the case of hepatitis C. Oncogene. 2006;25:3834–3847

    Article  PubMed  CAS  Google Scholar 

  89. Ahn SH, Park YN, Park JY, Chang HY, Lee JM, Shin JE,et al Long-term clinical and histological outcomes in patients with spontaneous hepatitis B surface antigen seroclearance. J Hepatol. 2005;42:188–194

    Article  PubMed  CAS  Google Scholar 

  90. Pollicino T, Squadrito G, Cerenzia G, Cacciola I, Raffa G, Craxi’ A, et al Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection. Gastroenterology. 2004;126:102–111

    Article  PubMed  CAS  Google Scholar 

  91. Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, Huang GT, Iloeje UH; REVEAL-HBV Study Group (2006) Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 295: 65–73

    Google Scholar 

  92. Chan HL, Hui AY, Wong ML, Tse AM, Hung LC, Wong VW, et al Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma. Gut. 2004;53: 1494–1498

    Article  PubMed  Google Scholar 

  93. Kao JH, Chen PJ, Lai MY, Chen DS. Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers. Gastroenterology. 2003;124:327–334

    Article  PubMed  CAS  Google Scholar 

  94. Kuang SY, Jackson PE, Wang JB, Lu PX, Munoz A,Qian GS, et al Specific mutations of hepatitis B virus in plasma predict liver cancer development. Proc Natl Acad Sci USA. 2004;101:3575–3580

    Article  PubMed  CAS  Google Scholar 

  95. Thorgeirsson S, Grisham J. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 2002;31:332–336.

    Article  CAS  Google Scholar 

  96. Staib F, Hussain SP, Hofseth LJ, Wang XW,Harris CC. TP53 and liver carcinogenesis. Hum Mutat. 2003;21:201–216

    Article  PubMed  CAS  Google Scholar 

  97. Aguilar F, Hussain SP, Cerutti P. Aflatoxin B1 induces the transversion of G–>T in codon 249 of the p53 tumor suppressor gene in human hepatocytes. Proc Natl Acad Sci U S A. 1993;90:8586–8590

    Article  PubMed  CAS  Google Scholar 

  98. Laurent-Puig P, Legoix P, Bluteau O, et al Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology. 2001;120:1763–1773

    Article  PubMed  CAS  Google Scholar 

  99. Boyault S, Rickman DS, de Reynies A, et al Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2007;45:42

    Article  PubMed  CAS  Google Scholar 

  100. Lee S, Lee HJ, Kim JH, et al Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol. 2003;163:1371–1377

    PubMed  CAS  Google Scholar 

  101. 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;117:2713–2722

    Article  PubMed  CAS  Google Scholar 

  102. Wei Y, Van Nhieu JT, Prigent S, et al Altered expression of E-cadherin in hepatocellular carcinoma: correlations with genetic alterations, b-catenin expression and clinicalfeatures. Hepatology. 2002;36:692–701

    Article  PubMed  CAS  Google Scholar 

  103. Li X, Hui AM, Sun L, et al pl6INK4A hypermethylation is associated with hepatitis B virus infection, age, and gender in hepatocellular carcinoma. Clin Cancer Res. 2004;10:7484–7491

    Article  PubMed  CAS  Google Scholar 

  104. Narimatsu T, Tamori A, Koh N, et al p16 promoter hypermethylation in human hepatocellular carcinoma with or without hepatitis virus infection. Intervirology. 2004; 47:26–31

    Article  PubMed  CAS  Google Scholar 

  105. Kremsdorf D, Soussan P, Paterlini-Brechot P, Brechot C. Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis. Oncogene. 2006;27:3823–3833

    Article  CAS  Google Scholar 

  106. Dvorchik I, Schwartz M, Fiel MI, et al Fractional allelic imbalance could allow for the development of an equitable transplant selection policy for patients with hepatocellular carcinoma. Liver Transpl. 2008;14:443–450

    Article  PubMed  Google Scholar 

  107. Aoki H, Kajino K, Arakawa Y, Hino O. Molecular cloning of a rat chromosome putative recombinogenic sequence homologous to the hepatitis B virus encapsidation signal. Proc Natl Acad Sci USA. 1996;93:7300–7304

    Article  PubMed  CAS  Google Scholar 

  108. Forgues M, Difilippantonio MJ, Linke SP, et al Involvement of Crm1 in hepatitis B virus X protein-induced aberrant centriole replication and abnormal mitotic spindles. Mol Cell Biol. 2003;23:5282–5292

    Article  PubMed  CAS  Google Scholar 

  109. Kawai H, Suda T, Aoyagi Y, et al Quantitative evaluation of genomic instability as a possible predictor for development of hepatocellular carcinoma: comparison of loss of heterozygosity and replication error. Hepatology. 2000;31: 1246–1250

    Article  PubMed  CAS  Google Scholar 

  110. Baek K, Park H, Kang K, et al Overexpression of hepatitis C virus NS5A protein induces chromosome Instability via mitotic cell cycle dysregulation. J Mol Biol. 2006;359:22–34

    Article  PubMed  CAS  Google Scholar 

  111. Marchio A, Pineau P, Meddeb M, et al Distinct chromosomal abnormality pattern in primary liver cancer of non-B, non-C patients. Oncogene. 2000;19:3733–3738

    Article  PubMed  CAS  Google Scholar 

  112. Wang J, Chenivesse X, Henglein B, Brechot C. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature. 1990;343:555–557

    Article  PubMed  CAS  Google Scholar 

  113. Gozuacik I, Murakami Y, Saigo K, et al Identification of human cancer-related genes by naturally occurring Hepatitis B Virus DNA tagging. Oncogene. 2001;20: 6233–6240

    Article  PubMed  CAS  Google Scholar 

  114. Ferber MJ, Montoya DP, Yu C, et al Integrations of the hepatitis B virus (HBV) and human papillomavirus (HPV) into the human telomerase reverse transcriptase (hTERT) gene in liver and cervical cancers. Oncogene. 2003;22:3813–3820

    Article  PubMed  CAS  Google Scholar 

  115. Paterlini-Brechot P, Saigo K, Murakami Y. Hepatitis B virus-related insertional mutagenesis occurs frequently in human liver cancers and recurrently targets human telomerase gene. Oncogene. 2003;22:3911–3916

    Article  PubMed  CAS  Google Scholar 

  116. 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;54:1162–1168

    Article  PubMed  CAS  Google Scholar 

  117. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–2576

    Article  PubMed  CAS  Google Scholar 

  118. Wiemann SU, Satyanarayana A, Tsahuridu M, et al Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. Faseb J. 2002;16: 935–942

    Article  PubMed  CAS  Google Scholar 

  119. Plentz RR, Park YN, Lechel A, et al Telomere shortening and inactivation of cell cycle checkpoints characteriz e human hepatocarcinogenesis. Hepatology. 2007;45: 968–976

    Article  PubMed  CAS  Google Scholar 

  120. Kojima H, Yokosuka O, Imazeki F, et al Telomerase activity and telomere length in hepatocellular carcinoma and chronic liver disease. Gastroenterology. 1997;112:493–500

    Article  PubMed  CAS  Google Scholar 

  121. Ozturk M, Arslan-Ergul A, Bagislar S et al (2008) Senescence and immortality in hepatocellular carcinoma. Cancer Lett

    Google Scholar 

  122. Janknecht R. On the road to immortality: hTERT upregulation in cancer cells. FEBS Lett. 2004;564:9–13

    Article  PubMed  CAS  Google Scholar 

  123. Terradillos O, Billet O, Renard CA, et al The hepatitis B virus X gene potentiates c-myc-induced liver oncogenesis in transgenic mice. Oncogene. 1997;14:395–404

    Article  PubMed  CAS  Google Scholar 

  124. Hsieh YH, Su IJ, Wang HC, Chang WW, Lei HY, Lai MD, et al Pre-S mutant surface antigens in chronic hepatitis B virus infection induce oxidative stress and DNA damage. Carcinogenesis. 2004;25:2023–2032

    Article  PubMed  CAS  Google Scholar 

  125. Hildt E, Munz B, Saher G, et al The PreS2 activator MHBs(t) of hepatitis B virus activates c-raf-1/Erk2 signaling in transgenic mice. EMBO J. 2002;21:525–535

    Article  PubMed  CAS  Google Scholar 

  126. Pang R, Lee TK, Poon RT, et al Pin1 interacts with a specific serine-proline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis. Gastroenterology. 2007;132:1088–1103

    Article  PubMed  CAS  Google Scholar 

  127. Park IY, Sohn BH, Yu E, et al Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein. Gastroenterology. 2007;132: 1476–1494

    Article  PubMed  CAS  Google Scholar 

  128. Jung JK, Arora P, Pagano JS, 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: 5771–5778

    Article  PubMed  CAS  Google Scholar 

  129. Zheng DL, Zhang L, Cheng N, Xu X, Deng Q, Teng XM, et al0 Epigenetic modification induced by hepatitis B virus X protein via interaction with de novo DNA methyltransferase DNMT3A. J Hepatol. 2009;50:377–387

    Article  PubMed  CAS  Google Scholar 

  130. Yu X, Mertz JE. Differential regulation of the pre-C and pregenomic promoters of human hepatitis B virus by members of the nuclear receptor superfamily. J Virol. 1997;71:9366–9374

    PubMed  CAS  Google Scholar 

  131. Chami M, Oulès B, Paterlini-Bréchot P. Cytobiological consequences of calcium-signaling alterations induced by human viral proteins. Biochimica et Biophysica Acta. 2006;1763:1344–1362

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Dipartimento di Medicina Interna, Sapienza Universita’ di Roma, Policlinico Umberto I, Viale del Policlinico 155, 0061, Rome, Italy

    Massimo Levrero & Laura Belloni

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  1. Massimo Levrero
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  2. Laura Belloni
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Correspondence to Massimo Levrero .

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  1. Inselspital, Universität Bern, Murtenstr. 35, Bern, 3010, Switzerland

    Jean-Francois Dufour

  2. Klinik für Viszeral- und, Universitätsspital Zürich, Rämistr. 100, Zürich, 8091, Switzerland

    Pierre-Alain Clavien

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Levrero, M., Belloni, L. (2010). HBV Signaling. In: Dufour, JF., Clavien, PA. (eds) Signaling Pathways in Liver Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00150-5_31

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