1887

Abstract

The genome of hepatitis B virus (HBV) consists of four open reading frames, encoding the envelope proteins (Pre-S/S), the core proteins (Pre-C/C), the polymerase (P) and the transactivating X protein (X). In the sera of HBV-infected patients, hepatitis B surface antigen (HBsAg) particles without the viral genome can outnumber virions by more than 1000-fold. To analyse the interactions between HBsAg and host cells, global gene-expression profiles of a small HBsAg (SHBs)-secreting stable cell line (HepG2-S-G2) and its counterpart control cell line (HepG2-Neo-F4) were compared. Marked upregulation of lymphoid enhancer-binding factor 1 (LEF-1), a transcription factor in the Wnt pathway, was found in SHBs-expressing cells and was confirmed by interference experiments with small interfering RNA. However, compared with the control cells, HepG2-S-G2 did not show higher proliferative competence in culture or increased tumorigenesis in nude mice. A possible mechanism to explain the discrepancy between the upregulation of LEF-1 and the lack of increased tumorigenesis is SHBs expression resulting in altered expression and distribution of LEF-1 protein in cell compartments and upregulation of LEF-1 isoforms that could suppress, rather than enhance, the Wnt pathway.

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2007-11-01
2021-08-02
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References

  1. Alexander J. J., Bey E. M., Geddes E. W., Lecatsas G. 1976; Establishment of a continuously growing cell line from primary carcinoma of the liver. S Afr Med J 50:2124–2128
    [Google Scholar]
  2. Beasley R. P., Shiao I. S., Wu T. C., Hwang L. Y. 1982; Hepatoma in an HBsAg carrier – seven years after perinatal infection. J Pediatr 101:83–84 [CrossRef]
    [Google Scholar]
  3. Cha M. Y., Kim C. M., Park Y. M., Ryu W. S. 2004; Hepatitis B virus X protein is essential for the activation of Wnt/ β -catenin signaling in hepatoma cells. Hepatology 39:1683–1693 [CrossRef]
    [Google Scholar]
  4. Cheng J., Imanishi H., Morisaki H., Liu W., Nakamura H., Morisaki T., Hada T. 2005; Recombinant HBsAg inhibits LPS-induced COX-2 expression and IL-18 production by interfering with the NF κ B pathway in a human monocytic cell line, THP-1. J Hepatol 43:465–471 [CrossRef]
    [Google Scholar]
  5. Chisari F. V., Klopchin K., Moriyama T., Pasquinelli C., Dunsford H. A., Sell S., Pinkert C. A., Brinster R. L., Palmiter R. D. 1989; Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell 59:1145–1156 [CrossRef]
    [Google Scholar]
  6. Clayton R. F., Owsianka A., Patel A. H. 2001; Evidence for structural differences in the S domain of L in comparison with S protein of hepatitis B virus. J Gen Virol 82:1533–1541
    [Google Scholar]
  7. Clevers H., van de Wetering M. 1997; TCF/LEF factors earn their wings. Trends Genet 13:485–489 [CrossRef]
    [Google Scholar]
  8. Cordray P., Satterwhite D. J. 2005; TGF- β induces novel Lef-1 splice variants through a Smad-independent signaling pathway. Dev Dyn 232:969–978 [CrossRef]
    [Google Scholar]
  9. Coyle-Rink J., Del Valle L., Sweet T., Khalili K., Amini S. 2002; Developmental expression of Wnt signaling factors in mouse brain. Cancer Biol Ther 1:640–645 [CrossRef]
    [Google Scholar]
  10. de La Coste A., Romagnolo B., Billuart P., Renard C. A., Buendia M. A., Soubrane O., Fabre M., Chelly J., Beldjord C. other authors 1998; Somatic mutations of the β -catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci U S A 95:8847–8851 [CrossRef]
    [Google Scholar]
  11. Ding Q., Xia W., Liu J. C., Yang J. Y., Lee D. F., Xia J., Bartholomeusz G., Li Y., Pan Y. other authors 2005; Erk associates with and primes GSK-3 β for its inactivation resulting in upregulation of β -catenin. Mol Cell 19:159–170 [CrossRef]
    [Google Scholar]
  12. Eastman Q., Grosschedl R. 1999; Regulation of LEF-1/TCF transcription factors by Wnt and other signals. Curr Opin Cell Biol 11:233–240 [CrossRef]
    [Google Scholar]
  13. Ganem D., Prince A. M. 2004; Hepatitis B virus infection – natural history and clinical consequences. N Engl J Med 350:1118–1129 [CrossRef]
    [Google Scholar]
  14. Giles R. H., van Es L. H., Clevers H. 2003; Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 16531–24
    [Google Scholar]
  15. Hildt E., Munz B., Saher G., Reifenberg K., Hofschneider P. H. 2002; The PreS2 activator MHBs(t) of hepatitis B virus activates c-raf-1/Erk2 signaling in transgenic mice. EMBO J 21:525–535 [CrossRef]
    [Google Scholar]
  16. Hovanes K., Li T. W., Waterman M. L. 2000; The human LEF-1 gene contains a promoter preferentially active in lymphocytes and encodes multiple isoforms derived from alternative splicing. Nucleic Acids Res 28:1994–2003 [CrossRef]
    [Google Scholar]
  17. Hovanes K., Li T. W., Munguia J. E., Truong T., Milovanovic T., Lawrence Marsh J., Holcombe R. F., Waterman M. L. 2001; β -Catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer. Nat Genet 28:53–57
    [Google Scholar]
  18. Kato T., Satoh S., Okabe H., Kitahara O., Ono K., Kihara C., Tanaka T., Tsunoda T., Yamaoka Y. other authors 2001; Isolation of a novel human gene, MARKL1 , homologous to MARK3 and its involvement in hepatocellular carcinogenesis. Neoplasia 3:4–9 [CrossRef]
    [Google Scholar]
  19. Khan N., Guarnieri M., Ahn S. H., Li J., Zhou Y., Bang G., Kim K. H., Wands J. R., Tong S. 2004; Modulation of hepatitis B virus secretion by naturally occurring mutations in the S gene. J Virol 78:3262–3270 [CrossRef]
    [Google Scholar]
  20. Lee W. M. 1997; Hepatitis B virus infection. N Engl J Med 337:1733–1745 [CrossRef]
    [Google Scholar]
  21. Lee T. K., Man K., Ho J. W., Wang X. H., Poon R. T., Xu Y., Ng K. T., Chu A. C., Sun C. K. other authors 2005; FTY720: a promising agent for treatment of metastatic hepatocellular carcinoma. Clin Cancer Res 11:8458–8466 [CrossRef]
    [Google Scholar]
  22. Lee H. C., Kim M., Wands J. R. 2006; Wnt/Frizzled signaling in hepatocellular carcinoma. Front Biosci 11:1901–1915 [CrossRef]
    [Google Scholar]
  23. Li Y., Wasser S., Lim S. G., Tan T. M. 2004; Genome-wide expression profiling of RNA interference of hepatitis B virus gene expression and replication. Cell Mol Life Sci 61:2113–2124
    [Google Scholar]
  24. Locarnini S., Shaw T., Dean J., Colledge D., Thompson A., Li K., Lemon S. M., Lau G. G., Beard M. R. 2005; Cellular response to conditional expression of the hepatitis B virus precore and core proteins in cultured hepatoma (Huh-7) cells. J Clin Virol 32:113–121 [CrossRef]
    [Google Scholar]
  25. Lupberger J., Hildt E. 2007; Hepatitis B virus-induced oncogenesis. World J Gastroenterol 13:74–81 [CrossRef]
    [Google Scholar]
  26. Milich D. R. 1997; Immune response to the hepatitis B virus: infection, animal models, vaccination. Viral Hepatitis Rev 3:63–103
    [Google Scholar]
  27. Nakanishi F., Ohkawa K., Ishida H., Hosui A., Sato A., Hiramatsu N., Ueda K., Takehara T., Kasahara A. other authors 2005; Alteration in gene expression profile by full-length hepatitis B virus genome. Intervirology 48:77–83 [CrossRef]
    [Google Scholar]
  28. Ng R. K., Lau C. Y., Lee S. M., Tsui S. K., Fung K. P., Waye M. M. 2004; cDNA microarray analysis of early gene expression profiles associated with hepatitis B virus X protein-mediated hepatocarcinogenesis. Biochem Biophys Res Commun 322:827–835 [CrossRef]
    [Google Scholar]
  29. Ocama P., Opio C. K., Lee W. M. 2005; Hepatitis B virus infection: current status. Am J Med 118:1413.e15–1413.e22
    [Google Scholar]
  30. Rehermann B., Nascimbeni M. 2005; Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 5:215–229 [CrossRef]
    [Google Scholar]
  31. Roberts L. R., Gores G. J. 2005; Hepatocellular carcinoma: molecular pathways and new therapeutic targets. Semin Liver Dis 25:212–225 [CrossRef]
    [Google Scholar]
  32. Schmitt-Graeff A., Ertelt-Heitzmann V., Allgaier H. P., Olschewski M., Nitschke R., Haxelmans S., Koelble K., Behrens J., Blum H. E. 2005; Coordinated expression of cyclin D1 and LEF-1/TCF transcription factor is restricted to a subset of hepatocellular carcinoma. Liver Int 25:839–847 [CrossRef]
    [Google Scholar]
  33. Seeger C., Mason W. S. 2000; Hepatitis B virus biology. Microbiol Mol Biol Rev 64:51–68 [CrossRef]
    [Google Scholar]
  34. Sells M. A., Chen M. L., Acs G. 1987; Production of hepatitis B virus particles in Hep G2 cells transfected with cloned hepatitis B virus DNA. Proc Natl Acad Sci U S A 84:1005–1009 [CrossRef]
    [Google Scholar]
  35. Shtutman M., Zhurinsky J., Simcha I., Albanese C., D'Amico M., Pestell R., Ben-Ze'ev A. 1999; The cyclin D1 gene is a target of the β -catenin/LEF-1 pathway. Proc Natl Acad Sci U S A 96:5522–5527 [CrossRef]
    [Google Scholar]
  36. Tetsu O., McCormick F. 1999; β -Catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398:422–426 [CrossRef]
    [Google Scholar]
  37. Vanlandschoot P., Leroux-Roels G. 2003; Viral apoptotic mimicry: an immune evasion strategy developed by the hepatitis B virus?. Trends Immunol 24:144–147 [CrossRef]
    [Google Scholar]
  38. Wang X., Seed B. 2003; A PCR primer bank for quantitative gene expression analysis. Nucleic Acids Res 31:e154 [CrossRef]
    [Google Scholar]
  39. Wang W., Ji P., Steffen B., Metzger R., Schneider P. M., Halfter H., Schrader M., Berdel W. E., Serve H., Muller-Tidow C. 2005; Alterations of lymphoid enhancer factor-1 isoform expression in solid tumors and acute leukemias. Acta Biochim Biophys Sin (Shanghai) 37:173–180 [CrossRef]
    [Google Scholar]
  40. Wen Y. M., Copeland J. A., Mann G. F., Howard C. R., Zuckerman A. J. 1981; Detection of HBsAg in a clone derived from the PLC/PRF/5 human hepatoma cell line. Arch Virol 68:157–163 [CrossRef]
    [Google Scholar]
  41. Wu C. G., Salvay D. M., Forgues M., Valerie K., Farnsworth J., Markin R. S., Wang X. W. 2001; Distinctive gene expression profiles associated with hepatitis B virus x protein. Oncogene 20:3674–3682 [CrossRef]
    [Google Scholar]
  42. Yang H. I., Lu S. N., Liaw Y. F., You S. L., Sun C. A., Wang L. Y., Hsiao C. K., Chen P. J., Chen D. S., Chen C. J. 2002; Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 347:168–174 [CrossRef]
    [Google Scholar]
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