Cancer Letters
Volume 286, Issue 1 , Pages 69-79 , 1 December 2009

Putative roles of hepatitis B x antigen in the pathogenesis of chronic liver disease

  • Mark A. Feitelson

      Affiliations

    • Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
    • Corresponding Author InformationCorresponding author. Tel.: +1 215 204 8434; fax: +1 215 204 8349.
  • ,
  • Helena M.G.P.V. Reis

      Affiliations

    • MIT Portugal Program, Av. Antonio Jose de Almeida, 12 1000-043 Lisboa, Portugal
  • ,
  • N. Lale Tufan

      Affiliations

    • Department of Medical Biology, Pamukkale University School of Medicine, Kinikli Denizli, Turkey
  • ,
  • Bill Sun

      Affiliations

    • Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
  • ,
  • Jingbo Pan

      Affiliations

    • Department of Pathology and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
  • ,
  • Zhaorui Lian

      Affiliations

    • Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA

Received 19 February 2008 ,Revised 18 November 2008 ,Accepted 2 December 2008.

References 

  1. Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and HBV. A prospective study of 22,707 men in Taiwan. Lancet. 1981;2:1129–1133
  2. Beasley RP, Hwang LY. Epidemiology of hepatocellular carcinoma. In:  Vyas GN,  Dienstag JL,  Hoofnagle JH editor. Viral Hepatitis and Liver Disease. New York: Grune and Stratton Inc.; 1984;p. 209–224
  3. Chisari FV, Ferrari C. Hepatitis B virus immunopathology. Springer Semin. Immunopathol. 1995;17:261–281
  4. Chisari FV, Ferrari C. Hepatitis B virus immunopathogenesis. Annu. Rev. Immunol. 1995;13:29–60
  5. Liaw YF. Hepatitis B virus replication and liver disease progression: the impact of antiviral therapy. Antivir. Ther. 2006;11:669–679
  6. Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN. REVEAL-HBV study group, risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65–73
  7. Hui AY, Friedman SL. Molecular basis of hepatic fibrosis. Expert Rev. Mol. Med. 2003;5:1–23
  8. Moreira RK. Hepatic stellate cells and liver fibrosis. Arch. Pathol. Lab. Med. 2007;131:1728–1734
  9. Sadek AG, Mitchell DG, Siegelman ES, Outwater EK, Matteucci T, Hann HW. Early hepatocellular carcinoma that develops within macroregenerative nodules: growth rate depicted at serial MR imaging. Radiology. 1995;195:753–756
  10. Mitchell DG, Rubin R, Siegelman ES, Burk DL, Rifkin MD. Hepatocellular carcinoma within siderotic regenerative nodules: appearance as a nodule within a nodule on MR images. Radiology. 1991;178:101–103
  11. 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
  12. 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
  13. Hoofnagle JH, Shafritz DA, Popper H. Chronic type B hepatitis and the “healthy” HBsAg carrier state. Hepatology. 1987;7:758–763
  14. 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;8:322–330
  15. Kim WH, Hong F, Jaruga B, Zhang SS, Fan SJ, Liang TJ, et al. Hepatitis B virus X protein sensitizes primary mouse hepatocytes to ethanol- and TNF-alpha-induce apoptosis by a caspase-3-dependent mechanism. Cell. Mol. Immunol. 2005;2:40–48
  16. Meyer M, Caselmann WH, Schluter V, Schrenk R, Hofschneider PH, Baeuerle PA. Hepatitis B virus transactivator MHBxt: activation of NF-κB selective inhibition by antioxidants and integral membrane localization. EMBO J. 1992;11:2991–3001
  17. Ohno H, Kaneko S, Kobayashi K, Murakami S. Human hepatitis B virus enhancer 1 is responsive to human interleukin-6. J. Med. Virol. 1997;52:413–418
  18. M.A. Feitelson, H.M.G.P.V. Reis, L.S. Tufan, J. Liu, M. Zhu, J. Pan, Z. Lian, Hepatitis B x antigen interference with tumor suppressor pathways in hepatocarcinognesis, in: J. Kobarg (Ed.), The Pleiotropic Functions of the Viral Protein HBx in HBV Infection and the Development of Liver Cancer. Research Signpost, Kerala, India, in press.
  19. M.A. Feitelson, H.M.G.P.V. Reis, J. Liu, Z. Lian, J. Pan, Hepatitis B virus X antigen (HBxAg) and cell cycle control in chronic infection and hepatocarcinogenesis, in: R. Zhao (Ed.), Frontiers in Bioscience. Viral Infection and Cell Cycle Control, vol. 10, 2005, pp. 1558–1572.
  20. Kim CM, Koike K, Saito I, Miyamura T, Jay G. HBx gene of HBV induces liver cancer in transgenic mice. Nature. 1991;351:317–320
  21. Koike K, Moriya K, Iino S, Yotsuyanagi H, Endo Y, Miyamura T, et al. High level expression of hepatitis B virus HBx gene and hepatocarcinogenesis in transgenic mice. Hepatology. 1994;19:810–819
  22. Popper H, Roth L, Purcell RH, Tennant BC, L Gerin J. Hepatocarcinogenicity of the woodchuck hepatitis virus. Proc. Natl. Acad. Sci. USA. 1987;84:866–870
  23. 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
  24. Zoulim F, Saputelli J, Seeger C. Woodchuck hepatitis virus X protein is required for viral infection in vivo. J. Virol. 1994;68:2026–2030
  25. Matsubara K, Tokino T. Integration of HBV DNA and its implications for hepatocarcinogenesis. Mol. Biol. Med. 1990;7:243–260
  26. 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;54:1162–1168
  27. 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. USA. 1984;81:5350–5354
  28. Poussin K, Kienes 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;80:497–505
  29. 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;8:518–523
  30. 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;22:3911–3916
  31. 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
  32. Feitelson MA, Lee JM. Hepatitis B virus integration, fragile sites, and hepatocarcinogenesis. Cancer Lett. 2007;252:157–170
  33. Diamantis ID, McGandy CE, Chen TJ, Liaw YF, Gudat F, Bianchi L. Hepatitis B X-gene expression in hepatocellar carcinoma. J. Hepatol. 1992;15:400–403
  34. 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;21:313–321
  35. Hohne M, Schaefer S, Seifer M, Feitelson MA, Paul D, Gerlich WG. Malignant transformation of immortalized hepatocytes by HBV DNA. EMBO J. 1990;9:1137–1145
  36. 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–S65
  37. Wang W, London WT, Lega L, Feitelson MA. HBxAg in liver from carrier patients with chronic hepatitis and cirrhosis. Hepatology. 1991;14:29–37
  38. Wang W, London WT, Feitelson MA. HBxAg in HBV carrier patients with liver cancer. Cancer Res. 1991;51:4971–4977
  39. 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;150:1141–1157
  40. Henkler F, Koshy R. Hepatitis B virus transcriptional activators: mechanisms and possible role in oncogenesis. J. Viral Hepat. 1996;3:109–121
  41. Takada S, Koike K. Trans-activation function of a 3′ truncated X gene-cell fusion product from integrated HBV DNA in chronic hepatitis tissues. Proc. Natl. Acad. Sci. USA. 1990;87:5628–5632
  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;3:545–552
  43. 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;120:1208–1214
  44. 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;38:262–267
  45. Tilg H, Kaser A, Moschen AR. How to modulate inflammatory cytokines in liver diseases. Liver Intl. 2006;26:1029–1039
  46. Takehara T, Hayashi N, Katayama K, Kasahara A, Fusamoto H, Kato M, et al. Two-dimensional flow cytometric analysis of intrahepatic lymphocyte subsets from patients with chronic hepatitis. Dig. Dis. Sci. 1991;36:87–91
  47. Mondelli M, Mieli-Vergani G, Bortolotti F, Cadrobbi P, Rortmann B, Alberti A, et al. Different mechanisms responsible for in vitro cell mediated cytotoxicity to autologous hepatocytes in children with autoimmune and HBsAg-positive chronic liver disease. J. Pediatr. 1985;106:899–906
  48. Kagi D, Vignauz F, Ledermann B, Burki K, Depraetere V, Nagata S, et al. Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science. 1994;265:528–530
  49. Hodgson PD, Grant MD, Michalak TI. Perforin and Fas/Fas ligand-mediated cytotoxicity in acute and chronic woodchuck viral hepatitis. Clin. Exp. Immunol. 1999;118:63–70
  50. Nakamoto Y, Guidotti LG, Pasquetto V, Schreiber RD, Chisari FV. Differential target cell sensitivity to CTL-activated death pathways in hepatitis B virus transgenic mice. J. Immunol. 1999;158:5692–5697
  51. Park YN, Chae KJ, Kim YB, Park C, Theise N. Apoptosis and proliferation in hepatocarcinogenesis related to cirrhosis. Cancer. 2001;92:2733–2736
  52. Ogasawara J, Watanabe-Fukunaga R, Adachi M, Matsuzawa A, Kasugai T, Kitamura Y, et al. Lethal effects of the anti-Fas antibody in mice. Nature. 1993;364:806–809
  53. Ni R, Matsuda YTomitaK, Ichihara A, Ishimura K, Ogasawara J, et al. Fas-mediated apoptosis in primary cultured mouse hepatocytes. Exp. Cell Res. 1994;215:332–337
  54. Luo KX, Zhu YF, Zhang LX, He HT, Wang XS, Zhang L. In situ investigation of Fas/FasL expression in chronic hepatitis B infection and related liver diseases. J. Viral Hepat. 1997;4:303–307
  55. Roskams T, Libbrecht L, van Dame B, Desmet V. Fas and Fas ligand: strong co-expression in human hepatocytes surrounding hepatocellular carcinoma; can cancer induce suicide in peritumoral cells?. J. Pathol. 2000;191:150–153
  56. Shin EC, Shin JS, Park JH, 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;82:587–591
  57. Hayashi N, Mita E. Involvement of Fas system-mediated apoptosis in pathogenesis of viral hepatitis. J. Viral Hepat. 1999;6:357–365
  58. Chinnaiyan AM, O’Rourke K, Tewari M, Dixit VM. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell. 1995;81:505–512
  59. Muzio M, Chinnaiyan AM, Kischkel FC, O’Rourke K, Shevchenk A, Ni J, et al. FLICE, a novel FADD-homologous ICE/CED 3-like protease, is recruited to the CD95 (Fas/APO-1) death inducing signaling complex. Cell. 1996;85:817–827
  60. Gupta S. Molecular steps of death receptor and mitochondrial pathways of apoptosis. Life Sci. 2001;69:2957–2964
  61. Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 1998;94:491–501
  62. Roy S, Nicholson DW. Cross-talk in cell death signaling. J. Exp. Med. 2000;192:F21–F25
  63. Chen GG, Lai PBS, Chak ECW, Xu H, Lee KM, Lau WY. Immunohistochemical analysis of proapoptotic Bid levels in chronic hepatitis, hepatocellular carcinoma and liver metastases. Cancer Lett. 2001;172:75–82
  64. Chen GG, Lai PBS, Chan PKS, Chak ECW, Yip JHY, Ho RLK, et al. Decreased expression of Bid in human hepatocellular carcinoma is related to hepatitis B virus X protein. Eur. J. Cancer. 2001;37:1695–1702
  65. 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):171–182
  66. 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;88:3275–3285
  67. Gottlob K, Fulco M, Levrero M, Greessmann A. The hepatitis B virus HBx protein inhibits caspase 3 activity. J. Biol. Chem. 1998;273:33347–33353
  68. Shih WL, Kuo ML, Chuang SE, Cheng AL, Doong SL. Hepatitis B virus X protein inhibits transforming growth factor-beta-induced apoptosis through the activation of phosphatidylinositol 3-kinase pathway. J. Biol. Chem. 2000;275:25858–25864
  69. Fang JW, Shen WW, Meager A, Lau JY. Activation of the tumor necrosis factor alpha system in the liver in chronic hepatitis B virus infection. Am. J. Gastroenterol. 1996;91:748–753
  70. Gonzalez-Amaro R, Garcia-Monzon C, Garcia-Buey L, Moreno-Otero R, Alonso JL, Yague E, et al. Induction of tumor necrosis factor α production by human hepatocytes in chronic viral hepatitis. J. Exp. Med. 1994;179:841–848
  71. Guang LX. Hepatitis B virus infection in monocytes and their functional changes in patients with chronic hepatitis B. Chin. Med. J. 1992;72:651–654
  72. Lara-Pezzi E, Majano PL, Gomez-Gonzalo M, Garcia-Monzon C, Moreno-Otero R, Levrero M, et al. The hepatitis B virus X protein up-regulates tumor necrosis factor α gene expression in hepatocytes. Hepatology. 1998;28:1013–1021
  73. Kim WH, Hong F, Jaruga B, Hu Z, Fan S, Liang TJ, et al. Additive activation of hepatic NF-κB by ethanol and HBx or HCV core protein: involvement of TNF-α receptor 1-independent and – dependent mechanisms. FASEB J. 2001;15:2551–2553
  74. Soussan P, Garreau F, Zylberberg A, Ferray C, Brechot C, Kremsdorf D. In vivo expression of a new hepatitis B virus protein encoded by a spliced RNA. J. Clin. Invest. 2000;105:55–60
  75. Soussan P, Tuveri R, Nalpas B, Garreau F, Zavala F, Masson A, et al. The expression of hepatitis B spliced protein (HBSP) encoded by a spliced hepatitis B virus RNA is associated with viral replication and liver fibrosis. J. Hepatol. 2003;38:343–348
  76. Kandemir O, Polat G, Sahin E, Bagdatoglu O, Camdeviren H, Kaya A. Fibronectin levels in chronic viral hepatitis and response of this protein to interferon therapy. Hepato-Gastroenterol. 2004;51:811–814
  77. Budkowska A, Bedossa P, Groh F, Louise A, Pillot J. Fibronectin of human liver sinusoids binds hepatitis B virus: identification by an anti-idiotypic antibody bearing the internal image of the pre-S2 domain. J. Virol. 1995;69:840–848
  78. Norton PA, Reis MGPV, Feitelson MA. Activation of fibronection gene expression by hepatitis B virus X antigen. J. Viral Hepat. 2004;11:332–341
  79. Lara-Pezzi E, Majano PL, Yanez-Mo M, Gomez-Gonzalo M, Carretero M, Moreno-Otero R, et al. Effect of the hepatitis B virus HBx protein on integrin-mediated adhesion to and migration on extracellular matrix. J. Hepatol. 2001;34:409–415
  80. Varner JA, Emerson DA, Juliano RL. Integrin alpha 5 beta 1 expression negatively regulates cell growth: reversal by attachment to fibronectin. Mol. Biol. Cell. 1995;6:725–740
  81. Klein NP, Schneider RJ. Activation of src family kinases by hepatitis B virus HBx protein and coupled signaling to ras. Mol. Cell Biol. 1997;17:6427–6436
  82. Lara-Pezzi E, Roche S, Andrisani OM, Sanchez-Madrid F, Lopez-Cabrera M. The hepatitis B virus protein induces adherens junction disruption in a src-dependent manner. Oncogene. 2001;20:3323–3331
  83. Myullyla R, Wang C, Keikkinen J, Juffer A, Lampela O, Risteli M, et al. Expanding the lysyl hydroxylase toolbox: new insights into the localization and activities of lysyl hydroxylase 3 (LH3). J. Cell. Physiol. 2007;212:323–329
  84. Salo AM, Wang C, Sipila L, Sormunen R, Vapola M, Kervinen P, et al. Lysyl hydroxylase 3 (LH3) modifies proteins in the extracellular space, a novel mechanism for matrix remodeling. J. Cell. Physiol. 2006;207:644–653
  85. Castilla A, Prieto J, Fausto N. Transforming growth factors beta 1 and alpha in chronic liver disease. Effects of interferon alpha therapy. New Engl. J. Med. 1991;324:933–940
  86. Liu F, Li B, Nan Y. The effect of serum TGFβ1 of patients with chronic hepatitis B in liver fibrosis. Chin. J. Hepatol. 1999;7:196–198
  87. Flisiak R, Al-Kadasi H, Jaroszewicz J, Prokopowicz D, Flisiak I. Effect of lamivudine treatment on plasma levels of transforming growth factor beta1, tissue inhibitor of metalloproteinases-1 and metalloproteinase-1 in patients with chronic hepatitis B. World J. Gastroenterol. 2004;10:2661–2665
  88. Oshikawa O, Tamjura S, Kawata S, Ito N, Tsushima H, Kiso S, et al. The effect of hepatitis B virus X gene expression on response to growth inhibition by transforming growth factor beta 1. Biochem. Biophys. Res. Commun. 1996;222:770–773
  89. Yoo YD, Ueda H, Park K, Flanders KC, Lee YI, Jay G, et al. Regulation of transforming growth factor-beta 1 expression by the hepatitis B virus (HBV) X transactivator. Role in HBV pathogenesis. J .Clin. Invest. 1996;97:388–395
  90. Pan J, Clayton MM, Feitelson MA. HBxAg promotes transforming growth factor β1 (TGFβ1) activity by up-regulation of TGFβ1 and down-regulation of alpha 2-macroglobulin. J. Gen. Virol. 2004;85:275–282
  91. Kakumu S, Ito Y, Takayanagi M, Yoshioka K, Wakita T, Ishikawa T, et al. Effect of recombinant human transforming growth factor beta 1 on immune responses in patients with chronic hepatitis B. Liver. 1993;13:62–68
  92. Ljumovic D, Diamantis I, Alegakis AK, Kouroumalis EA. Differential expression of matrix metalloproteinases in viral and non-viral chronic liver diseases. Clin. Chim. Acta. 2004;349:203–211
  93. Yu FL, Liu HJ, Lee JW, Liao MH, Shih WL. Hepatitis B virus X protein promotes cell migration by inducing matrix metalloproteinase-3. J. Hepatol. 2005;42:520–527
  94. Lara-Pezzi E, Gome-Gaviro MV, Galvez BG, Mira E, Iniguez MA, Fresno M, et al. The hepatitis B virus X protein promotes tumor cells invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression. J. Clin. Invest. 2002;110:1831–1838
  95. Chung TW, Lee YC, Kim CH. Hepatitis B viral HBx induces matrix metalloproteinase 9 gene expression through activation of ERKs and PI3K/AKT pathways: involvement of invasive potential. FASEB J. 2004;18:1123–1125
  96. Chung TW, Moon SK, Lee YC, Kim JG, Ko JH, Kim CH. Enhanced expression of matrix metalloproteinase-9 by hepatitis B virus infection in liver cells. Arch. Biochem. Biophys. 2002;408:147–154
  97. Kim JR, Kim CH. Association of high activity of matrix metalloproteinase-9 to low levels of tissue inhibitors of metalloproteinase-1 and -3 in human hepatitis B – viral hepatoma cells. Int. J. Biochem. Cell Biol. 2004;36:2293–2306
  98. Yin SS, Li XM, Wang BE, Wang TL, Jia JD, Qian LX. The relationship of serum metalloproteinase with the severity of liver fibrosis and inflammation. Chin. J. Hepatol. 2004;12:666–668
  99. Han YP. Matrix metalloproteinases, the pros and cons, in liver fibrosis. J. Gastroenterol. Hepatol. 2006;21:S88–S91
  100. Flisiak R, Maxwell P, Prokopowicz D, Timms PM, Panasiuk A. Plasma tissue inhibitor of metalloproteinases-1 and transforming growth factor beta-1: possible non-invasive biomarkers of hepatic fibrosis in patients with chronic B and C hepatitis. Hepato-Gastroenterol. 2002;49:1369–1372
  101. Farrell GC, Teoh NC. Management of chronic hepatitis B virus infection: a new era of disease control. Int. Med. J. 2006;36:100–113
  102. Takehara T, Hayashi N, Mita E, Kanto T, Tatsumi T, Sasaki Y, et al. Delayed Fas-mediated hepatocytes apoptosis during liver regeneration in mice: hepatoprotective role of TNF alpha. Hepatology. 1998;27:1643–1651
  103. 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;4:1711–1717
  104. Diao J, Garces R, Richardson CD. X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis. Cytokine Growth Factor Rev. 2001;12:189–205
  105. Mahe Y, Mukaida N, Kuno K, Akiyama M, Ikeda N, Matsushima K, et al. Hepatitis B virus X protein transactivates human interleukin-8 gene through acting on nuclear factor kB and CCAAT/enhancer-binding protein-like cis-elements. J. Biol. Chem. 1991;266:13759–13763
  106. Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Ann. Rev. Cell Dev. Biol. 2001;17:463–516
  107. 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;37:380–386
  108. Puren AJ, Fantuzzi O, Gu Y, Su MS, Dinarello CA. Interleukin-18 (IFNgamma-inducing factor) induces IL-8 and IL-1beta via TNFalpha production from non-CD14+ human blood mononuclear cells. J. Clin. Invest. 1998;101:711–721
  109. Tsutsui H, Nakanishi K, Matsui K, Higashino K, Okamura H, Miyazawa Y, et al. IFN-gamma-inducing factor up-regulates Fas ligands mediated cytotoxic activity of murine natural killer cell clones. J. Immunol. 1996;157:3967–3973
  110. Dao T, Ohashi K, Kayano T, Kurimoto M, Okamura H. Interferon-gamma-inducing factor, a novel cytokine, enhances Fas ligand-mediated cytotoxicity of murine T helper 1 cells. Cell. Immunol. 1996;173:230–235
  111. Yu DY, Moon HB, Son JK, Jeong S, Yu SL, Yoon H. Incidence of hepatocellular carcinoma in transgenic mice expressing the hepatitis B virus X protein. J. Hepatol. 1999;31:123–132
  112. Huang X, Yu C, Jin C, Kobayashi M, Bowles CA, Wang F, et al. Ectopic activity of fibroblast growth factor receptor 1 in hepatocytes accelerates hepatocarcinogenesis by driving proliferation and vascular endothelial growth factor-induced angiogenesis. Cancer Res. 2006;66:1481–1490
  113. Qiu WH, Zhou BS, Chu PG, Chen WG, Chung C, Shih J, et al. Over-expression of fibroblast growth factor receptor 3 in human hepatocellular carcinoma. World J. Gastroenterol. 2005;11:5266–5272
  114. Nicholes K, Guillet S, Tomlinson E, Hillan K, Wright B, Frantz GD, et al. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am. J. Pathol. 2002;160:2295–2307
  115. Feng SL, Guo Y, Factor VM, Thorgeirsson SS, Bell DW, Testa JR, et al. The Fn14 immediate-early response gene is induced during liver regeneration and highly expressed in both human and murine hepatocellular carcinomas. Am. J. Pathol. 2000;156:1253–1261
  116. Zhang BB, Cai WM, Weng HL, Hu ZR, Lu J, Zheng M, et al. Diagnostic value of platelet derived growth factor-BB, transforming growth factor-beta1, matrix metalloproteinase-1, and tissue inhibitor of matrix metalloproteinase-1 in serum and peripheral blood mononuclear cells for hepatic fibrosis. World J. Gastroenterol. 2003;9:2490–2496
  117. Lou SM, Li YM, Wang KM, Cai WM, Weng HL. Expression of platelet-derived growth factor-BB in liver tissues of patients with chronic hepatitis B. World J. Gastroenterol. 2004;10:385–588
  118. Campbell JS, Hughes SD, Gilbertson DG, Palmer TE, Holdren MS, Haran AC, et al. Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc. Natl. Acad. Sci. USA. 2005;102:3389–3394
  119. Martin-Vilchez S, Sanz-Cameno P, Rodriguez-Munoz Y, Majano PL, Molina-Jimenez F, Lopez-Cabrera M, et al. The hepatitis B virus X protein induces paracrine activation of human hepatic stellate cells. Hepatology. 2008;47:1872–1883
  120. Sanz-Cameno P, Martin-Vilchez S, Lara-Pezzi E, Borque MJ, Salmeron J, Munoz de Rueda P, et al. Hepatitis B virus promotes angiopoietin-2 expression in liver tissue: role of HBV x protein. Am. J. Pathol. 2006;169:1215–1222
  121. Gutierrez-Reyes G, Gutierrez-Ruiz MC, Kershenobich D. Liver fibrosis and chronic viral hepatitis. Arch. Med. Res. 2007;38:644–651
  122. Akhurst RJ. TGF-beta antagonists: why suppress a tumor suppressor?. J. Clin. Invest. 2002;109:1533–1536

PII: S0304-3835(08)00931-2

doi: 10.1016/j.canlet.2008.12.010

Cancer Letters
Volume 286, Issue 1 , Pages 69-79 , 1 December 2009