Interactive Effects of p53 Tumor Suppressor Gene and Hepatitis B Virus in Hepatocellular Carcinogenesis

  • Libin Jia
  • Xin Wei Wang
  • Zongtang Sun
  • Curtis C. Harris


Chronic infection with hepatitis B (HBV) or C (HCV) virus and dietary exposure to either aflatoxin B1 or alcoholic beverages are the major risk factors of hepatocellular carcinoma (HCC). Mutations in the p53 tumor suppressor gene are frequently found in HCC. Aflatoxin B1 exposure also has a positive correlation with codon 249ser mutation of the p53 tumor suppressor gene. The continued expression of hepatitis B virus X protein (HBx) plays an important role in hepatocellular carcinogenesis. The protein—protein interaction between the HBx and p53 tumor suppressor protein can abrogate the normal functions of p53. This review discusses the role of the p53 tumor suppressor gene and its interactive effects with HBx in human liver carcinogenesis.


Human Immunodeficiency Virus Type 
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  1. 1.
    Di Bisceglie AM, Rustgi VK, Hoofnagle JH, Dusheiko GM, Lotze MT (1988) Hepatocellular carcinoma. Ann Intern Med 108:390–401PubMedCrossRefGoogle Scholar
  2. 2.
    Feitelson MA (1986) HBV and cancer. In Notkins AL, Oldstone MBA (eds) Concepts in Viral Pathogenesis II. Springer, Berlin Heidelberg New York, pp 269–275Google Scholar
  3. 3.
    Popper H, Shafritz DA, Hoofnagle JH (1987) Relation of hepatitis B virus carrier state to hepatocellular carcinoma. Hepatology 7:764–772PubMedCrossRefGoogle Scholar
  4. 4.
    Ganem D, Varmus HE (1987) The molecular biology of the hepatitis B viruses. Annu Rev Biochem 56:651–693PubMedCrossRefGoogle Scholar
  5. 5.
    Wogan WN (1992) Aflatoxins as risk factors for hepatocellular carcinoma in humans. Cancer Res 52:2114s–2118sPubMedGoogle Scholar
  6. 6.
    Harris CC (1990) Hepatocellular carcinogenesis: recent advances and speculation. Cancer Cell 2:146–148Google Scholar
  7. 7.
    Ross RK, Yuan JM, Yu MC, Wogan GN, Qian GS, Tu JT, Groopman, JD, Gao YT, Henderson BE (1992) Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma. Lancet 339:943–946PubMedCrossRefGoogle Scholar
  8. 8.
    Bishop JM (1991) Molecular themes in oncogenesis. Cell 164:235–248CrossRefGoogle Scholar
  9. 9.
    Weinberg RA (1991) Tumor suppressor genes. Science 254:1138–1146PubMedCrossRefGoogle Scholar
  10. 10.
    Harris CC (1990) Chemical and physical carcinogenesis: advances and perspectives for the 1990s. Cancer Res 51:5023s–5044sGoogle Scholar
  11. 11.
    Levine AJ, Momand J, Finlay CA (1991) The p53 tumor suppressor gene. Nature 351:453–456PubMedCrossRefGoogle Scholar
  12. 12.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49–53PubMedCrossRefGoogle Scholar
  13. 13.
    Greenblatt MS, Bennett WP, Hollstein M, Harris CC (1994) Mutations in the p53 tumour suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54:4855–4878PubMedGoogle Scholar
  14. 14.
    Soussi T, Fromental C, Mary P (1990) Structural aspects of the p53 protein in relation to gene to gene evolution. Oncogene 5:945–952PubMedGoogle Scholar
  15. 15.
    Malkin D, Li F, Strong L, Fraumeni J, Nelson C, Kim D, Kassel J, Gryka M, Biochoff F, Tainsky M, Friend S (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcoma, and other neoplasms. Science 250:1233–1238PubMedCrossRefGoogle Scholar
  16. 16.
    Lane DP, Benchimol S (1990) p53: oncogene or antioncogene. Genes Dev 4:1–8PubMedCrossRefGoogle Scholar
  17. 17.
    Dittmer D, Patis S, Zambettig, Chus S, Teresdy AK, Moore M, Finlay C, Levine AJ (1993) Gain of function mutations in p53. Nature Genet 4: 42–46PubMedCrossRefGoogle Scholar
  18. 18.
    Hsiao M, Low J, Dorn E, Ku D, Pattengale P, Yeargin J, Haas M (1994) Gain-of-function mutations of the p53 gene induce lymphohematopoietic metastatic potential and tissue invasiveness. Am J Pathol 145:702–714PubMedGoogle Scholar
  19. 19.
    Eliyahu D, Michalovitz D, Eliyahu S, Pinhasi Kimhi O, Oren M (1989) Wild-type p53 can inhibit oncogene-mediated focus formation. Proc Natl Acad Sci USA 86:8763–8767PubMedCrossRefGoogle Scholar
  20. 20.
    Finlay CA, Hinds PW, Levine AJ (1989) The p53 proto-oncogene can act as a suppressor of transformation. Cell 57:1083–1093PubMedCrossRefGoogle Scholar
  21. 21.
    Baker SJ, Markowitz S, Fearon ER, Willson JK, Vogelstein B (1992) Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249:912–915CrossRefGoogle Scholar
  22. 22.
    Diller L, Kassel J, Nelson CE, Grayka MA, Ligwak G, Gebhardt M, Bressac B, Ozturk M, Baker SJ, Vogelstein B (1990) p53 functions as a cell cycle control protein in osteosarcomas. Mol Cell Biol 10:5772–5781PubMedGoogle Scholar
  23. 23.
    Mercer WE, Shields MT, Amin M, Sauve GJ, Appella E, Romano JW, Ullrich SJ (1990) Negative growth regulation in a glioblastoma tumor cell line that conditionally expresses human wild-type p53. Proc Natl Acad Sci USA 87:6166–6170PubMedCrossRefGoogle Scholar
  24. 24.
    Chen PL, Chen Y, Bookstein R, Lee WH (1991) Genetic mechanisms of tumor suppression by the human p53 gene. Science 250:1576–1580CrossRefGoogle Scholar
  25. 25.
    Bressac B, Kew M, Wands J, Ozturk M (1991) Selective G to T mutations of p.53 gene in hepatocellular carcinoma from southern Africa. Nature 350:429–431PubMedCrossRefGoogle Scholar
  26. 26.
    Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC (1991) Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature 350:427–428PubMedCrossRefGoogle Scholar
  27. 27.
    Scorsone KA, Zhou YZ, Butel JS, Slagle BL (1992) p53 Mutations cluster at codon 249 in hepatitis B virus-positive hepatocellular carcinomas from China. Cancer Res 52:1635–1638PubMedGoogle Scholar
  28. 28.
    Li D, Cao Y, He L, Wang NJ, Gu J (1993) Aberrations of p53 gene in human hepatocellular carcinoma from China. Carcinogenesis 14:169–173PubMedCrossRefGoogle Scholar
  29. 29.
    Aguilar F, Harris CC, Sun T, Hollstein M, Cerutti P (1994) Geographic variation of p53 mutational profile in nonmalignant human liver. Science 264:1317–1319PubMedCrossRefGoogle Scholar
  30. 30.
    Aguilar F, Hussain SP, Cerutti P (1993) Aflatoxin B induces the transversion of G → T in codon 249 of the p53 tumor suppressor gene in human hepatocytes. Proc Natl Acad Sci USA 90:8586–8590PubMedCrossRefGoogle Scholar
  31. 31.
    Ponchel F, Puisieux A, Tabone E, Michot JP, Froschl G, Morel AP, Frebourg T, Fontaniere B, Oberhammer F, Ozturk M (1994) Hepatocarcinoma-specific mutant p53-249ser induces mitotic activity but has no effect on transforming growth factor beta 1-mediated apoptosis. Cancer Res 54:2064–2068PubMedGoogle Scholar
  32. 32.
    Forrester K, Lupold SE, Ott VL, Chay CH, Wang XW, Harris CC (1995) Effects of p53 mutants on wild-type p53-mediated transactivation are cell type dependent. Oncogene 10:2103–2111PubMedGoogle Scholar
  33. 33.
    Maguire HF, Hoeffler JP, Siddiqui A (1991) HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein—protein interactions. Science 252:842–844PubMedCrossRefGoogle Scholar
  34. 34.
    Twu JS, Schloemer RH (1987) Transcriptional transactivating function of hepatitis B virus. J Virol 61:3448–3453PubMedGoogle Scholar
  35. 35.
    Spandau DF, Lee CH (1988) Trans-activation of viral enhancers by the hepatitis B virus X protein. J Virol 62:427–434PubMedGoogle Scholar
  36. 36.
    Shirakata Y, Kawada M, Fujiki Y, Sano H, Oda M, Yagnuma K, Kobayashi M, Koike K (1989) The X gene of hepatitis B virus induced growth stimulation and tumorigenic transformation of mouse NIH3T3 cells. Jpn J Cancer Res 80:617–621PubMedCrossRefGoogle Scholar
  37. 37.
    Caselmann WH, Meyer M, Kekule AS, Lauer U, Hofschneider PH, Koshy R (1990) A transactivator function is generated by integration of hepatitis B virus preS/S sequences in human hepatocellular carcinoma DNA. Proc Natl Acad Sci USA 87:2970–2974PubMedCrossRefGoogle Scholar
  38. 38.
    Kekule AS, Lauer U, Meyer M, Caselmann WH, Hofschnelder PH, Koshy R (1990) The preS2/S region of integrated hepatitis B virus DNA encodes a transcriptional transactivator. Nature 343:457–461PubMedCrossRefGoogle Scholar
  39. 39.
    Benn J, Schneider RJ (1994) Hepatitis B virus HBx protein activates Ras—GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade. Proc Natl Acad Sci USA 91: 10350–10354PubMedCrossRefGoogle Scholar
  40. 40.
    Unsal H, Yakicier C, Marcais C, Kew M, Volkmann M, Zentgraf H, Isselbacher KJ, Ozturk M (1994) Genetic heterogeneity of hepatocellular carcinoma. Proc Natl Acad Sci USA 91:822–826PubMedCrossRefGoogle Scholar
  41. 41.
    Paterlini P, Poussin K, Kew M, Franco D, Brechot C (1995) Selective accumulation of the X transcript of hepatitis B virus in patients negative for hepatitis B surface antigen with hepatocellular carcinoma. Hepatology 21:313–321PubMedGoogle Scholar
  42. 42.
    Feitelson MA, Zhu M, Duan LX, London WT (1993) Hepatitis B X antigen and p53 are associated in vitro and in liver tissues from patients with primary hepatocellular carcinoma. Oncogene 8:1109–1117PubMedGoogle Scholar
  43. 43.
    Wang XW, Forrester K, Yeh H, Feitelson MA, Gu JR, Harris CC (1994) Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding transcriptional activity and association with transcription factor ERCC3. Proc Natl Acad Sci USA 91:2230–2234PubMedCrossRefGoogle Scholar
  44. 44.
    Ueda H, Ullrich SJ, Gangemi JD, Kappel CA, Ngo L, Feitelson MA, Jay G (1995) Functional inactivation but not structural mutation of p.53 causes liver cancer. Nature Genet 9:41–47PubMedCrossRefGoogle Scholar
  45. 45.
    Wang XW, Gibson MK, Vermeulen W, Yeh H, Forrester K, Sturzbacher H-W, Hoeijmakers JHJ, Harris CC (1995) Abrogation of p53-induced apoptosis by the hepatitis B virus X gene. Cancer Res 55:6012–6016PubMedGoogle Scholar
  46. 46.
    Hino O, Nomura K, Ohtake K, Kawaguchi T, Sugano H, Kitagawa T (1989) Instability of integrated hepatitis B virus DNA with inverted repeat structure in a transgenic mouse. Cancer Genet Cytogenet 37:273–278PubMedCrossRefGoogle Scholar
  47. 47.
    Hino O, Tabata S, Hotta Y (1991) Evidence for increased in vitro recombination with insertion of human hepatitis B virus DNA. Proc Natl Acad Sci USA 88:9248–9252PubMedCrossRefGoogle Scholar
  48. 48.
    Tiollais P, Pourcel C, Dejean A (1985) The hepatitis B virus. Nature 317:489–495PubMedCrossRefGoogle Scholar
  49. 49.
    Moriarty AM, Alexander H, Lerner RA, Thornton GB (1985) Antibodies to peptides detect new hepatitis B antigen: serological correlation with hepatocellular carcinoma. Science 227:429–432PubMedCrossRefGoogle Scholar
  50. 50.
    Kim C, Koike K, Saito L, Miyamura T, Jay G (1991) HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 351:317–320PubMedCrossRefGoogle Scholar
  51. 51.
    Matsubara K, Tokino T (1990) Integrating of hepatitis B virus DNA and its implications for hepatocarcinogenesis. Mol Biol Med 7:243–260PubMedGoogle Scholar
  52. 52.
    Seto E, Mitchell PJ, Yen TSB (1990) Transactivation by the hepatitis B virus X protein depends on AP-2 and other transcription factors. Nature 344:72–74PubMedCrossRefGoogle Scholar
  53. 53.
    Twu J-S, Lai M-Y, Chen D-S, Robinson WS (1993) Activation of protooncogene c-jun by the X protein of hepatitis B virus. Virology 192:346–450PubMedCrossRefGoogle Scholar
  54. 54.
    Kekule AS, Lauer U, Weiss L, Luber B, Hofschneider PH (1993) Hepatitis B virus transactivator HBx uses a tumour promoter signaling pathway. Nature 361:742–745PubMedCrossRefGoogle Scholar
  55. 55.
    Natoli G, Avantaggiati ML, Chirillo P, Costanzo A, Artini M, Balsano C, Levero M (1994) Induction of the DNA-binding activity of c-jun/c-fos heterodimers by the hepatitis B virus transactivator pX. Mol Cell Biol 14:989–998 56. Seto E, Yen TSB, Peterlin BM, Ou J-H (1988) Trans-activation of the human immunodeficiency virus long terminal repeat by the hepatitis B virus X protein. Proc Natl Acad Sci USA 85:8286–8290Google Scholar
  56. 57.
    Twu J-S, Wu JY, Robinson WS (1990) Transcription activation of the human immunodeficiency virus type 1 long terminal repeat by hepatitis B virus X-protein requires de novo protein synthesis. Virology 177:406–410PubMedCrossRefGoogle Scholar
  57. 58.
    Levrero M, Balsano C, Natoli G, Avantaggiati ML, Elfassi E (1990) Hepatitis B virus X protein transactivates the long terminal repeats of human immunodeficiency virus type 1 and 2. J Virol 64:3082–3086PubMedGoogle Scholar
  58. 59.
    Lucito R, Schneider RJ (1992) Hepatitis B virus X protein activates transcription factor NF-κB without a requirement for protein kinase C. J Virol 66:983–991PubMedGoogle Scholar
  59. 60.
    Aufiero B, Schneider RJ (1990) The hepatitis B virus X-gene product trans-activates both RNA polymerase II and III promoters. EMBO J 9:497–504PubMedGoogle Scholar
  60. 61.
    Doria M, Klein N, Lucito R, Schneider RJ (1995) The hepatitis B virus HBx protein is a dual specificity cytoplasmic activator of Ras and nuclear activator of transcription factors. EMBO J 14:4747–4757PubMedGoogle Scholar
  61. 62.
    Haviv I, Vaizel D, Shaul Y (1995) The X protein of hepatitis B virus coactivates potent activation domains. Mol Cell Biol 15:1079–1086PubMedGoogle Scholar
  62. 63.
    Maguire HF, Hoeffler JP, Siddiqui A (1991) HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions. Science 252:842–844PubMedCrossRefGoogle Scholar
  63. 64.
    Williams JS, Andrisani OM (1995) The hepatitis B virus X protein targets the basic region-leucine zipper domain of CREB. Proc Natl Acad Sci USA 92:3819–3823PubMedCrossRefGoogle Scholar
  64. 65.
    Kern SE, Kinzler KW, Bruskin A, Jarosz D, Friedman P, Prives C, Vogelstein B (1991) Identification of p53 as a sequence-specific DNA-binding protein. Science 252:1708–1711PubMedCrossRefGoogle Scholar
  65. 66.
    Qadri I, Maguire HF, Siddiqui A (1995) Hepatitis B virus transactivator protein X interacts with the TATA-binding protein. Proc Natl Acad Sci USA 92:1003–1007PubMedCrossRefGoogle Scholar
  66. 67.
    El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75:817–825PubMedCrossRefGoogle Scholar
  67. 68.
    Harper JW, Adami GR, Wei N, Keyomarisi K, Elledge SJ (1993) The p21 cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.Cell 75:805–816PubMedCrossRefGoogle Scholar
  68. 69.
    Kern SE, Pietenpol JA, Thiagalingam S, Seymour A, Kinzler KW, Vogelstein B (1992) Oncogenic forms of p53 inhibit p53-regulated gene expression. Science 256:827–830PubMedCrossRefGoogle Scholar
  69. 70.
    Cross JC, Wen P, Rutter WJ (1993) Transactivation by hepatitis B virus X protein is promiscuous and dependent on mitogen activated cellular serine/ threonine kinase. Proc Natl Acad Sci USA 90:8078–8082PubMedCrossRefGoogle Scholar
  70. 71.
    Schaeffer L, Roy R, Humbert S, Moncollin V, Vermeulen W, Hoeijmakers JH, Chambon P, Egly JM (1993) DNA repair helicase: a component of BTF2 (TFIIH) basic transcription factor. Science 260:58–63PubMedCrossRefGoogle Scholar
  71. 72.
    Lee TH, Elledge SJ, Butel JS (1995) Hepatitis B virus X protein interacts with a probable cellular DNA repair protein. J Virol 69:1107–1114PubMedGoogle Scholar
  72. 73.
    Lane DP (1992) Cancer: p53, guardian of the genome. Nature 358:15–16PubMedCrossRefGoogle Scholar
  73. 74.
    Lane DP, Crawford LV (1979) T antigen is bound to a host protein in SV40-transformed cells. Nature 278:261–263PubMedCrossRefGoogle Scholar
  74. 75.
    Linzer DI, Levine AJ (1979) Characterization of a 54 K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17:43–52PubMedCrossRefGoogle Scholar
  75. 76.
    Werness BA, Levine AJ, Howley PM (1990) Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248:76–79PubMedCrossRefGoogle Scholar
  76. 77.
    Szekely L, Selivanova G, Magnusson KP, Klein G, Wiman KG (1993) EBNA-5, an Epstein-Barr virusencoded nuclear antigen, binds to the retinoblastoma and p53 proteins. Proc Natl Acad Sci USA 90:5455–5459PubMedCrossRefGoogle Scholar
  77. 78.
    Speir E, Modali R, Huang ES, Leon MB, Shawl F, Finkel T, Epstein SE (1994) Potential role of human cytomegalovirus and p53 interaction in coronary restenosis. Science 265:391–394PubMedCrossRefGoogle Scholar
  78. 79.
    McCarthy SA, Symonds HS, Van Dyke T (1994) Regulation of apoptosis in transgenic mice by simian virus 40 T antigen-mediated inactivation of p53. Proc Natl Acad Sci USA 91:3979–3983PubMedCrossRefGoogle Scholar
  79. 80.
    Debbas M, White E (1993) Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. Genes Dev 7:546–554PubMedCrossRefGoogle Scholar
  80. 81.
    Wyllie AH (1994) Apoptosis: death gets a brake. Nature 369:272–273PubMedCrossRefGoogle Scholar
  81. 82.
    Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257PubMedCrossRefGoogle Scholar
  82. 83.
    Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T (1993) p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362:847–849PubMedCrossRefGoogle Scholar
  83. 84.
    Clarke AR, Puridie CA, Harrison, Morris RG, Bird CC, Hooper ML, Wyllie AH (1993) Thymocyte apoptosis induced by p53-dependent and independ-ent pathways. Nature 362:849–852PubMedCrossRefGoogle Scholar
  84. 85.
    Lowe SW, Ruley HE, Jacks T, Housman DE (1992) p53-dependent apoptosis modulates the cytotoxic-ity of anticancer agents. Cell 74:957–967CrossRefGoogle Scholar
  85. 86.
    Symonds H, Krall L, Remington L, Saenz-Robles M, Lowe S, Jacks T, Van Dyke T (1994) p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell 78:703–711PubMedCrossRefGoogle Scholar
  86. 87.
    Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE, Housman DE, Jacks T (1994) p53 status and the efficacy of cancer therapy in vivo. Science 266:807–810PubMedCrossRefGoogle Scholar
  87. 88.
    Benn J, Schneider RJ (1995) Hepatitis B virus HBx protein deregulates cell cycle checkpoint controls. Proc Natl Acad Sci USA 92:11215–11219PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 1997

Authors and Affiliations

  • Libin Jia
    • 1
  • Xin Wei Wang
    • 1
  • Zongtang Sun
    • 1
  • Curtis C. Harris
    • 1
  1. 1.Laboratory of Human Carcinogenesis, Division of Basic Sciences, National Cancer InstituteNational Institutes of HealthBethesdaUSA

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