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Tumorvirus HBV: Transaktiverung zellulärer Genexpression durch Hepatitis-B-Virusproteine

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Molekularbiologische Grundlagen der Gastroenterologie

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Zusammenfassung

Epidemiologische Daten weisen auf die Bedeutung der chronischen Hepatitis-B-Virus-(HBV-)infektion für die Entstehung des primären hepatozellulären Karzinoms (HCC) hin. Auf molekularer Ebene sind HBV-Sequenzen häufig in Leberzell-DNA integriert. Im Gegensatz zum Waldmurmeltiermodell, in dem eine spezifische Integration viraler DNA in der Mehrzahl der Fälle nachweisbar ist, scheint die insertionelle (In)aktivierung zellulärer Gene beim Menschen ein äußerst seltenes Ereignis zu sein.

Die Entdeckung transaktivierender Funktionen, die durch das HBx und carboxyterminal trunkierte Oberflächenproteine (HBst) ausgeübt werden, stellt ein attraktives Konzept der HBV-assoziierten Leberzellkarzinomentstehung dar. Transaktivatorsequenzen werden in 81% (21 von 26) HCCs oder Hepatomzellinien gefunden. In allen bisher untersuchten Fällen ist zumindest einer dieser Transaktivatoren funktionell aktiv.

Im Gegensatz zu HBx ist eine carboxyterminale Trunkierung erforderlich, um MHBst-Transaktivatoren zu generieren. Diese werden im Unterschied zum intakten MHBs im endoplasmatischen Retikulum retiniert und nicht ins Zellkulturmedium sezerniert. Sie stimulieren die zelluläre Genexpression von den Regulatorsequenzen der humanen Protoonkogene c-fos und c-myc sowie dem Promotor des hepatischen Akutphaseproteins Interleukin-6. Synthetische Bindungsstellen für die Transkriptionsfaktoren NF-κB, AP-1, AP-2, SRE und Sp1 vermitteln den Transeffekt. Die NF-κB-abhägige Transaktivierung durch MHBst kann durch Antioxidanzien inhibiert werden, was einen indirekten Hinweis auf die Beteiligung reaktiver Sauerstoffintermediate darstellt.

Zusammenfassed bieten diese Daten indirekte Evidenz, daß HBV-Transaktivatoren an der Leberzellkarzinogenese beteiligt sind.

Summary

Epidemiological data support the crucial role of chronic hepatitis B virus (HBV) infection in hepatocellular carcinoma (HCC) development. On the molecular level HBV sequences are frequently integrated in hepatocellular DNA. However, in contrast to the woodchuck model, in which specific HBV DNA integration is detectable in the majority of cases, insertional (in-)äctivation of cellular genes seems to be a rare event in men.

The recent discovery of transactivating functions exerted by HBx and truncated HBs(urface) proteins supported the notion that activation of cellular gene expression in trans could be relevant for hepatocarcinogenesis. HBV transactivator sequences are present in 81% (21 out of 26) HCC tissues or hepatoma-derived cell lines. At least one transactivator protein is functional in all cases investigated so far.

In contrast to HBx, HBs transactivators require carboxyterminal truncation to gain their transactivating function. Unlike full-length M(iddle)HBs the truncated MHBst is retained in the endoplasmic reticulum and not secreted into the surrounding medium. Cellular gene expression is stimulated from regulatory elements of the human proto-oncogenes c-fos and c-myc as well as the hepatic acute phase gene interleukin-6. Synthetic binding sites for the transcripton factors NF-κB, AP-1, AP-2, SRE and Sp1 render minimal promotors activatable. NF-κB-mediated transactivation by MHBst can be suppressed by radical scavanging antioxidants indirectly suggesting that reactive oxygen intermediates are involved.

In summary, the data provide indirect evidence that transactivating effects exerted by HBV proteins may contribute to the multistep pathogenesis of HCC development.

Teile der dargestellten experimentellen Daten wurden im Rahmen der Dissertation von Dr. Markus Meyer und Herrn Volker Schlüter unter meiner Anleitung in der Abteilung Virusforschung (Direktor Prof. Dr. Dr. P.H. Hofschneider) des Max-Planck-Instituts für Biochemie in Martinsried erhoben. Die Arbeiten wurden durch Mittel des Bundesministeriums für Forschung und Technologie, Deutsche Stiftung für Krebshilfe (W21/8/Hol-Prof. Dr. Dr. Hofschneider) und der Deutschen Forschungsgemeinschaft (Ca-113/5-2-PD Dr. Caselmann) unterstützt.

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Literatur

  1. Bäuerle PA, Baltimore D (1988) Activation of DNA-binding activity in an apparently cytoplasmic precursor of the NF-κB transcription factor. Cell 53:211–217.

    Article  Google Scholar 

  2. Balch WE (1990) Molecular dissection of early stages of the eukaryotic secretory pathway. Curr Opin Cell Biol 2:634–641.

    Article  PubMed  CAS  Google Scholar 

  3. Bauskin AR, Alkalay I, Ben-Neriah Y (1991) Redox regulation of a protein tyrosine kinase in the endoplasmic reticulum. Cell 66:685–696.

    Article  PubMed  CAS  Google Scholar 

  4. Beasley RP (1988) Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer 61:1942–1956.

    Article  PubMed  CAS  Google Scholar 

  5. Budkowska A, Riottot MM, Dubreuil P, Lazizi Y, Brechot C, Sobczak E, Petit MA, Pillot J (1986) Monoclonal antibody recognizing preS2 epitope of hepatitis B virus: characterization of preS2 epitope and anti-preS2 antibody. J Med Virol 20:111–125.

    Article  PubMed  CAS  Google Scholar 

  6. Caselmann WH, Meyer M, Kekulé AS, Lauer U, Hofschneider PH, Koshy R (1990) A novel trans-activator is encoded by hepatitis B virus preS/S sequences integrated in human hepatocellular carcinoma DNA. Proc Natl Acad Sci USA 87:2970–2974.

    Article  PubMed  CAS  Google Scholar 

  7. Caselmann WH (1995) Transactivation of cellular gene expression by hepatitis B viral proteins: a possible molecular mechanism of hepatocarcinogenesis. J Hepatol 22 [Suppl. 1]:34–37.

    PubMed  CAS  Google Scholar 

  8. Chisari FV, Klopchin K, Moriyama T, Pasquinelli C, Dunsford HA, Sell S, Pinkert CA, Brinster RL, Palmiter RD (1989) Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell 59:1145–1156.

    Article  PubMed  CAS  Google Scholar 

  9. Cohen JI, Kieff E (1991) An Epstein-Barr virus nuclear protein 2 domain essential for transformation is a direct transcriptional activator. J Virol 65:5880–5885.

    PubMed  CAS  Google Scholar 

  10. De Thé H, Marchio A, Tiollais P, Dejean A (1987) A novel steroid thyroid hormone receptor-related gene inappropriately expressed in human hepatocellular carcinoma. Nature 330:667–670.

    Article  PubMed  Google Scholar 

  11. Fourel G, Couturier J, Wei Y, Apiou F, Tiollais P, Buendia MA (1994) Evidence for long-range oncogene activation by hepadnavirus insertion. EMBO J 13:2526–2534.

    PubMed  CAS  Google Scholar 

  12. Fujiki Y, Hubbard AL, Fowler S, Lazarow PB (1982) Isolation of intracellular membranes by means of sodium carbonate treatment: application to endplasmic reticulum. J Cell Biol 93:97–102.

    Article  PubMed  CAS  Google Scholar 

  13. Gerbes AL, Caselmann WH (1993) Point mutations in the p53 gene, human hepatocellular carcinoma and aflatoxins. J Hepatol 19:312–315.

    Article  PubMed  CAS  Google Scholar 

  14. Gething MJ, McCammon K, Sambrook J (1986) Expression of wild-type and mutant forms of influenca hemagglutinin: the role of folding in intracellular transport. Cell 46:939–950.

    Article  PubMed  CAS  Google Scholar 

  15. Gräf E, Caselmann WH, Wells J, Koshy R (1994) Insertional activation of mevalonate kinase by hepatitis B virus DNA in a human hepatoma cell line. Oncogene 9:81–87.

    Google Scholar 

  16. Gräf E, Caselmann WH, Hofschneider PH, Koshy R (1995) Enzymatic properties of overexpressed HBV-mevalonate kinase fusion proteins and mevalonate kinase proteins in the human hepatoma cell line PLC/PRF/5. Virology 208:696–703.

    Article  Google Scholar 

  17. Hildt E, Urban S, Lauer U, Hofschneider PH, Kekulé AS (1993) ER localization and functional expression of the HBV transactivator MHBst. Oncogene 1993; 8:3359–3367.

    CAS  Google Scholar 

  18. Höhne M, Schaefer S, Seifer 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  Google Scholar 

  19. Kekulé AS, Lauer U, Meyer M, Caselmann WH, Hofschneider PH, Koshy R (1990) The preS2/S region of integrated hepatitia B virus-DNA encodes a transcriptional trans-activator. Nature 343:457–461.

    Article  PubMed  Google Scholar 

  20. Kekulé AS, Lauer U, Weiss L, Luber B, Hofscneider PH (1993) Hepatitis B virus trans-activator HBx uses a tumour promoter signalling pathway. Nature 361:742–745.

    Article  PubMed  Google Scholar 

  21. Kim CM, 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 

  22. Koch S, Freytag von Loringhoven A, Hofschneider PH, Koshy R (1984) Amplification and rearrangement in hepatoma cell DNA associated with integrated hepatitis B virus DNA. EMBO J 3:2185–2189.

    PubMed  CAS  Google Scholar 

  23. Lauer U, Weiß L, Hofschneider PH, Kekulé AS (1992) The hepatitis B virus trans-activator is generated by 3′ truncation within a defined region of the S gene. J Virol 66:5284–5289.

    PubMed  CAS  Google Scholar 

  24. Lauer U, Weiss L, Lipp M, Hofschneider PH, Kekulé AS (1994) The hepatitis B virus preS2/St transactivator utilizes AP-1 and other transcription factors for transactivation. Hepatology 19:23–31.

    PubMed  CAS  Google Scholar 

  25. Liebermann TA, Baltimore D (1990) Activation of interleukin-6 expression through the NF-κB transcription factor. Mol Cell Biol 10:2327–2334.

    Google Scholar 

  26. Luber B, Bürgelt E, Fromental C, Kanno M, Koch W (1991) Multiple Simian Virus 40 enhancer elements mediate the trans-activating function of the X protein of hepatitis B virus. Virol 184:80–873.

    Google Scholar 

  27. Meyer M, Caselmann WH, Schlüter V, Schreck R, Hofschneider PH, Baeuerle PA (1992) Hepatitis B virus trans-activator MHBxt: activation of NF-κB, selective inhibition by antioxidants and integral membrane localization. EMBO J 11:2991–3001.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  29. 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 carcinoma. Genes Dev 1:773–782.

    Article  PubMed  CAS  Google Scholar 

  30. Natoli G, Avantaggiati ML, Balsano C, De Marizio E, Collepardo D, Elfassi E, Levrero M (1992) Characterization of the hepatitis B virus preS/S region encoded transcrip-tional trans-activator. Virology 187:663–670.

    Article  PubMed  CAS  Google Scholar 

  31. Raychaudhuri P, Bagchi S, Devoto SH, Kraus VB, Moran E, Nevins JR (1991) Domains of the adenovirus ELA protein required for oncogenic activity are also required for dissociation of the E2F transcription factor complex. Genes Dev 5:1200–1211.

    Article  PubMed  CAS  Google Scholar 

  32. Schlüter V, Meyer M, Hofschneider PH, Koshy R, Caselmann WH (1994) Integrated hepatitis B virus X and 3′ truncated preS/S sequences derived from human hepatomas encode functionally active transactivators. Oncogene 9:3335–3344.

    PubMed  Google Scholar 

  33. Schlüter V, Caselmann WH (im Druck) Analysis of the nuclear DNA binding activity in cells overexpressing hepatitis B viral x and 3′ truncated transactivators. Method Mol Genetics.

    Google Scholar 

  34. Shimizu H, Mitomo K, Watanabe T, Okamoto S, Yamamoto K (1990) involvement of a NF-κB-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines. Mol Cell Biol 10:561–568.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  36. Summers J, Smolec JM, Snyder R (1978) A virus similar to human hepatitis B virus associated with hepatitis and hepatoma in woodchucks. Proc Natl Acad Sci USA 75:4533–4537.

    Article  PubMed  CAS  Google Scholar 

  37. Szmuness W (1978) Hepatocellular carcinoma and the hepatitis B Virus: evidence for a causal association. Prog Med Virol 24:40–69.

    PubMed  CAS  Google Scholar 

  38. Twu JR, Schlömer RH (1987) Transcriptional trans-activating function of hepatitis B virus. J Virol 61:3448–3453.

    PubMed  CAS  Google Scholar 

  39. Wang J, Chenivesse X, Henglein B, Bréchot C (1990) Hepatitis B virus integration in a cyclic A gene in a hepato-cellular carcinoma. Nature 343:555–557.

    Article  PubMed  CAS  Google Scholar 

  40. Wei Y, Fourel G, Ponzetto A, Silvestro M, Tiollais P, Buendia MA (1992) Hepadnavirus integration: mechanisms of activation of the N-myc2 retrotransposon in woodchuck liver tumors. J Virol 66:5265–5276.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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Authors
  1. W. H. Caselmann
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Editors and Affiliations

  1. Chirurgische Klinik I, Universität Ulm, Steinhövelstr. 9, 89075, Ulm, Deutschland

    Hans G. Beger

  2. Abteilung Gastroenterologie, Medizinische Hochschule Hannover, Konstanty-Gutschow-Str. 8, 30625, Hannover, Deutschland

    Michael P. Manns

  3. I. Medizinische Universitäts-Klinik, Martinistr. 52, 20251, Hamburg, Deutschland

    Heiner Greten

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© 1995 Springer-Verlag Berlin Heidelberg

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Caselmann, W.H. (1995). Tumorvirus HBV: Transaktiverung zellulärer Genexpression durch Hepatitis-B-Virusproteine. In: Beger, H.G., Manns, M.P., Greten, H. (eds) Molekularbiologische Grundlagen der Gastroenterologie. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-79782-8_9

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  • DOI: https://doi.org/10.1007/978-3-642-79782-8_9

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-59325-6

  • Online ISBN: 978-3-642-79782-8

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