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Hepatocarcinogenic Mechanisms in Hepadnavirus-infected Hosts

  • Conference paper
Viral Hepatitis and Liver Disease

  • 22 Accesses

Abstract

Chronic hepadnavirus infection is associated with hepatocellular carcinoma (HCC) in natural hosts including humans, woodchucks, and Beechey ground squirrels. Several possible oncogenic mechanisms have been identified. These include a potential role of the hepatitis B virus (HBV) X (hbx) gene which has been shown to transactivate transcription regulated by certain cis-acting sequences including regulatory sequences of HBV and heterologous regulatory sequences of other viruses and cellular genes. The diversity of regulatory sequences that appear to be activated by hbx suggests that the hbx protein acts by a general mechanism that is not DNA sequence-specific. The oncogenic potential of hbx is suggested by the observation of HCC in hbx transgenic mice, oncogenic transformation of cells expressing hbx in culture, and transactivation of oncogenes c-myc and c-jun by hbx. Cis-activation of cellular oncogenes N-myc and c-myc by viral promoter insertion has been observed in woodchuck hepatitis virus (WHV)-associated HCC in woodchucks by Buendia, Tiollais, et al. No such cis-activation of any cellular gene has been shown in virus-associated HCC of ground squirrels or humans. Amplification and overexpression of the c-myc gene has been found in some HCC of ground squirrels but not in woodchuck or human HCC. Point mutations in the p53 gene and allelic deletion of p53 have been found in some human HCC but not in HCC of woodchucks or ground squirrels.

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References

  1. Beasley RP, Lin CC, Hwang LY, et al. (1981) Hepatocellular carcinoma and hepatitis B virus: A prospective study of 22,707 men in Taiwan. Lancet 2: 1129–1133

    Article  PubMed  CAS  Google Scholar 

  2. Gerin JL (1990) Experimental WHV infection of woodchucks: An animal model of hepadnavirus-induced liver cancer. Gastroenterol Jpn 25 [Suppl]: 38–42

    PubMed  Google Scholar 

  3. Korba BE, Wells FV, Baldwin B, Cote PJ, Tennant BC, Popper H, Gerin JL (1989) Hepatocellular carcinoma in woodchuck hepatitis virus-infected woodchucks: Presence of viral DNA in tumor tissue from chronic carriers and animals serologically recovered from acute infections. Hepatology 9: 461–470

    Article  PubMed  CAS  Google Scholar 

  4. Marion PL, Van Davelaar MJ, Knight SS, Salazar FH, Garcia G, Popper H, Robinson WS (1983) Hepatocellular carcinoma in ground squirrels persistently infected with ground squirrel hepatitis virus. Proc Natl Acad Sci USA 83: 4543–4546

    Article  Google Scholar 

  5. Tiollais P, Pourcel C, Dejean A (1985) The hepatitis B virus. Nature 317: 489–490

    Article  PubMed  CAS  Google Scholar 

  6. Nagaya T, Nakamura T, Tokino T, Tsurimoto T, Imai M, Mayumi T, Kamino K, Yamamura K, Matsubara K (1987) The mode of hepatitis B virus DNA integration in chromosomes of human hepatocellular carcinome. Genes Dev 1: 773–782

    Article  PubMed  CAS  Google Scholar 

  7. Matsubara K, Tokina T (1990) Integration of hepatitis B virus DNA and its implications for hepatocarcinogenesis. Mol Biol Med 7: 243–260

    PubMed  CAS  Google Scholar 

  8. Dejean A, Bougueleret L, Grzeschik KH, Tiollais P (1986) Hepatitis B virus DNA integration in a sequence homologous to v-erb A and steroid receptor genes in a hepatocellular carcinoma. Nature 322: 70–72

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  10. Morov T, Marchio A, Etiemble J, Trepo C, Tiollais P, Buendia MA (1986) Rearrangement and enhanced expression of c-myc in hepatocellular carcinoma of hepatitis virus infected woodchucks. Nature 324: 276–279

    Article  Google Scholar 

  11. Hsu T, Moroy T, Etiemble J, Louise A, Trepo C, Tiollais P, Buendia MA (1988) Activation of c-myc by woodchuck hepatitis virus insertion in hepatocellular carcinoma. Cell 55: 627–635

    Article  PubMed  CAS  Google Scholar 

  12. Etiemble J, Moroy T, Jacquemin E, Tiollais P, Buendia MA (1989) Fused oranscripts of c-myc and a new cellular locus, her in a primary liver tumor. Oncogene 4: 51–57

    PubMed  CAS  Google Scholar 

  13. Fourel G, Trepo C, Bouqueleret L, Hemalein B, Pouzetto A, Tiollais P, Buendia M (1990) Frequent activation of N-myc gene by hepadnavirus insertion in woodchuck liver tumors. Nature 347: 294–298

    Article  PubMed  CAS  Google Scholar 

  14. Fung G-K, Lai CL, Todd D, Ganem D, Varmus HE (1984) An amplified domain of cellular DNA containing a subgenomic insert of hepatitis B virus DNA in a human hepatoma. In: Vyas G, Dienstag JL, Hoofnagle JH (eds) Viral hepatitis and liver disease: The 1984 International Symposium on Viral Hepatitis, Grune and Stratton, New York, p 633

    Google Scholar 

  15. Fung G-K, Lai CL, Lok A, Todd D, Varmus HE (1985) Analysis of HBV-associated human hepatocellular carcinoma for oncogene expression and structure rearrangement. In: Varmus H (ed) Molecular biology of hepatitis B viruses: Abstracts of papers presented at the 1985 meeting on molecular biology of hepatitis B viruses, May 2–5, 1985, Cold Spring Harbor Laboratory, N.Y.

    Google Scholar 

  16. Transy C, Fourel G, Robinson WS, Tiollais P (1992) Frequent amplification of c-myc in ground squirrel liver tumors associated with past or ongoing infection with a hepadnavirus. Proc Natl Acad Sci USA 89: 3874–3878

    Article  PubMed  CAS  Google Scholar 

  17. Hansen LJ, Tennant BC, Seeger C, Ganem D (1993) Differential activation of myc gene family members in hepatic carcinogenesis by closely related hepatitis B viruses. Mol Cel Biol 13: 659–667

    CAS  Google Scholar 

  18. Twu JS, Schloemer RH (1987) Transcriptional transactivating functions of hepatitis B virus. J Virology 61: 3448–3453

    PubMed  CAS  Google Scholar 

  19. Twu S Jr, Robinson WS (1989) Hepatitis B virus X gene can transactivate heterologous viral sequences. Proc Natl Acad Sci USA 86: 2046–2050

    Article  PubMed  CAS  Google Scholar 

  20. Seto E, Yen TS, Peterlin BM, Ou JH (1988) Trans-activation of the human immunodeficiency virus long terminal repeat by the hepatitis B virus X protein. Proc Natl Acad Sci 85: 8286–8290

    Article  PubMed  CAS  Google Scholar 

  21. Siddiqui A, Gaynor R, Srinivasan A; Mapoles J, Farr RW (1989) Trans-activation of viral enhances including long terminal repeat of the human immunodeficiency virus by the hepatitis B virus X protein. Virology 169: 479–484

    Article  PubMed  CAS  Google Scholar 

  22. Spandau DF, Lee CH (1988) Trans-activation of viral enhancers by the hepatitis B virus X protein. J Virol 62: 427–434

    PubMed  CAS  Google Scholar 

  23. Twu JS, Chu K, Robinson WS (1989) Hepatitis B virus x-gene activates icB-like enhancer sequences in HIV-1 LTR. Proc Natl Acad Sci USA 86: 5168–5172

    Article  PubMed  CAS  Google Scholar 

  24. Zahm P, Hofschneider P, Koshy R (1988) The HBV X-ORF encodes a transactivator: A potential factor in viral hepatocarcinogenesis. Oncogene 3: 169–177

    PubMed  CAS  Google Scholar 

  25. Twu JS, Rosen CA, Haseltine WA, Robinson WS (1989) Identification of a region within the human immunodeficiency virus (HIV-1) long terminal repeat (LTR) that is essential for trans-activation by the hepatitis B virus ( HBV) Gene X. J Virol 63: 2857–2860

    PubMed  CAS  Google Scholar 

  26. Koike K, Kobayashi M, Yaginama K, Shirakata Y (1987) Structure and function of integrated HBV DNA. In: Robinson WS, Koike K, Will H (eds) Hepadnaviruses Liss, New York, pp 267–286

    Google Scholar 

  27. Koike K, Shirakata Y, Yaginuma K, Arii M, Takada S, Nakamura I, Hayashi Y, Kawada M, Kobayashi M (1989) Oncogenic potential of hepatitis B virus. Mol Biol Med 6: 151–160

    PubMed  CAS  Google Scholar 

  28. Twu JS, Lai M-Y, Chen D-H, Robinson WS (1993) Activation of protooncogene c-jun by the x protein of hepatitis B virus. Virology 192: 346–350

    Article  PubMed  CAS  Google Scholar 

  29. Seto E, Mitchell J, Yen SB (1990) Transactivation by the hepatitis B virus x protein depends on AP-2 and other transcription factors. Nature 344: 72–74

    Article  PubMed  CAS  Google Scholar 

  30. Zhou D-X, Taraboulos A, Ou J-H, Benedictyen TS (1990) Activation of class I major histocompatibility complex gene expression by hepatitis B virus. J Virol 64: 4025–4028

    PubMed  CAS  Google Scholar 

  31. Wu J-Y, Zhou ZY, Judd A, Cartweight CA, Robinson WS (1990) The hepatitis B virus-encoded transcriptional transactivator hbx appears to be a novel serine/threonine kinase. Cell 63: 687–695

    Article  PubMed  CAS  Google Scholar 

  32. Seto E, Zhou D-X, Peterlin BM, Benedictyen TS (1989) Trans- activation by the hepatitis B virus x protein shows cell-type specificity. Virology 173: 764 - 766

    Article  PubMed  CAS  Google Scholar 

  33. Hohne M, Schaefer S, Scifer M, Feitelson MA, Paul D, Gerlich WH (1990) Malignant transformation of immortalized transgenic hepatocytes after transfection with hepatitis B virus DNA. EMBO J 9: 1137–1145

    PubMed  CAS  Google Scholar 

  34. Kim C-M, Koike K, Saito I, Miyamura T, Jay G (1991) HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 351: 317–320

    Article  PubMed  CAS  Google Scholar 

  35. Takada S, Koike K (1990) Trans-activation function of a 3′ truncated X gene-cell fusion product from integrated hepatitis B virus DNA in chronic hepatitis tissues. Proc Natl Acad Sci USA 87: 5628–5632

    Article  PubMed  CAS  Google Scholar 

  36. Wollersheim M, Debelka U, Hofschneider PH (1988) A trans-activating function encoded in the hepatitis B virus X gene is conserved in the integrated state. Oncogene 3: 545–552

    PubMed  CAS  Google Scholar 

  37. Kekule AS, Lauer U, Meyer M, Caselmann WH, Hofschneider PH, Koshy R (1990) The preS2/S region of integrated hepatitis B virus DNA encodes a transcriptional transactivator. Nature 343: 457–461

    Article  PubMed  CAS  Google Scholar 

  38. 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: 2970–2974

    Article  PubMed  CAS  Google Scholar 

  39. Trowbridge R, Fagan EA, Davison F, Eddleston ALWF, Williams R, Linskens MHK, Farzaneh F (1988) Amplification of the c-myc gene locus in a human hepatic tumor containing integrated hepatitis B virus DNA. In: Zuckerman A J (ed) Viral hepatitis and liver disease. Liss, New York, pp 764–768

    Google Scholar 

  40. 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: 427–428

    Article  PubMed  CAS  Google Scholar 

  41. Bressac B, Kew M, Wands J, Ozturk M (1991) Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350: 429–431

    Article  PubMed  CAS  Google Scholar 

  42. Hosono S, Lee CS, Chou MJ, Yang CS, Shih CH (1991) Molecular analysis of the p53 alleles in primary hepatocellular carcinomas and cell lines. Oncogene 6: 237–243

    PubMed  CAS  Google Scholar 

  43. Ozturk M (1991) p53 mutation in hepatocellular carcinoma after aflatoxin exposure. Lancet 338:1356–1359

    Google Scholar 

  44. Slagle BL, Zhou Y-Z, Butel JS (1991) Hepatitis B virus integration event in human chromosome 17p near the p53 gene identifies the region of the chromosome commonly deleted in virus-positive hepatocellular carcinomas. Cancer Res 51: 49–54

    PubMed  CAS  Google Scholar 

  45. Fujimori M, Tokino T, Hino O, Kitagawa T, Imamura T, Okamoto E, Mitsunobu M, Ishikawa T, Nakagama H, Harada H (1991) Allelotype study of primary hepatocellular carcinoma. Cancer Res 51: 89–93

    PubMed  CAS  Google Scholar 

  46. Bressac B, Galvin KM, Liang TJ, Isselbacher KJ, Wands JR, Ozturk M (1990) Abnormal structure and expression of p53 gene in human hepatocellular carcinoma. Proc Natl Acad Sci USA 87: 1973–1977

    Article  PubMed  CAS  Google Scholar 

  47. Hino O, Shows TB, Rogler CE (1986) Two integrated hepatitis B virus (HBV) DNA molecules were cloned from two primary hepatocellular carcinomas each contianing only a single integration. One integration (C3) contained a single linear segment of HBV DNA, and the other integration ( C4) contained a large inverted duplication of viral DNA at the site of a chromosome translocation. Proc Natl Acad Sci USA 83: 8338–8342

    Article  PubMed  CAS  Google Scholar 

  48. Meyer M, Wiedorn KH, Hofscneider PH, Koshy R, Caselmann WH (1992) A chomosome 17:7 translocation is associated with a hepatitis B virus DNA integration in human hepatocellular carcinoma DNA. Hepatology 15: 665–671

    Article  PubMed  CAS  Google Scholar 

  49. Gu JR (1988) Molecular aspects of human hepatic carcinogenesis. Carcinogenesis 9: 697

    Article  PubMed  CAS  Google Scholar 

  50. Yuasa Y, Sudo K (1987) Transforming genes in human hepatomas detected by a tumorigenicity assay. Jpn J Cancer Res 78: 1036

    PubMed  CAS  Google Scholar 

  51. Nakagama H, Ohnishi S, Imawari M, Hirai H, Takaku F, Sakamoto H, Terada M, Nagao M, Sugimura T (1987) Identification of transforming genes as hst in DNA samples from two human hepatocellular carcinomas. Jpn J Cancer Res 78: 651

    PubMed  CAS  Google Scholar 

  52. Ochiya T, Fujiyama A, Fukushige S, Hatada I, Matsubara K (1986) Molecular cloning of an oncogene from a human hepatocellular carcinoma. Proc Natl Acad Sci USA 83: 4993

    Article  PubMed  CAS  Google Scholar 

  53. Robinson WS (1993) The role of hepatitis B virus in development of primary hepatocellular carcinoma: Part II. J Gastroenterol Hepatol 8: 95–106

    Article  PubMed  CAS  Google Scholar 

  54. Robinson WS (1992) The role of hepatitis B virus in the development of primary hepatocellular carcinoma. Part. I. J Gastroenterol Hepatol 7: 622–638

    CAS  Google Scholar 

  55. Cerutti PA (1988) Response modification creates promotability in multistage carcinogenesis. Carcinogenesis 9: 519–526

    Article  PubMed  CAS  Google Scholar 

  56. Vesselinovitch SD, Mihailovich N (1983) Kinetics of diethylnitrosamine hepatocarcinogenesis in the infant mouse. Cancer Res 43: 4253

    PubMed  CAS  Google Scholar 

  57. Scherer E (1984) Neoplastic progression in experimental hepatocarcinogenesis. Biochim Biophys Acta 738: 219

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA

    William S. Robinson M.D.

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  1. William S. Robinson M.D.
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Editors and Affiliations

  1. Japanese Red Cross, Tokyo, Japan

    K. Nishioka M.D. (Chairman of 1993 ISVHLD) (Chairman of 1993 ISVHLD)

  2. Yamanashi Medical College, Yamanashi, Japan

    H. Suzuki (Vice Chairman of 1993 ISVHLD) (Vice Chairman of 1993 ISVHLD)

  3. Institute of Immunology, Tokyo, Japan

    S. Mishiro (Committee Member of 1993 ISVHLD) (Committee Member of 1993 ISVHLD)

  4. Japanese Red Cross Medical Center, Tokyo, Japan

    T. Oda (Honorary Chairman of 1993 ISVHLD) (Honorary Chairman of 1993 ISVHLD)

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© 1994 Springer-Verlag Tokyo

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Robinson, W.S. (1994). Hepatocarcinogenic Mechanisms in Hepadnavirus-infected Hosts. In: Nishioka, K., Suzuki, H., Mishiro, S., Oda, T. (eds) Viral Hepatitis and Liver Disease. Springer, Tokyo. https://doi.org/10.1007/978-4-431-68255-4_8

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  • DOI: https://doi.org/10.1007/978-4-431-68255-4_8

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-68257-8

  • Online ISBN: 978-4-431-68255-4

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