1887

Abstract

The Epstein–Barr virus (EBV)-encoded EBNA1 protein is expressed in all virus-associated tumours, including nasopharyngeal carcinoma (NPC), where it plays an essential role in EBV genome maintenance, replication and transcription. Previous studies suggest that EBNA1 may have additional effects relevant to oncogenesis, including enhancement of cell survival, raising the possibility that EBNA1 may influence cellular gene expression. We have recently demonstrated by gene expression microarray profiling in an NPC cell model that EBNA1 influences the expression of a range of cellular genes, including those involved in transcription, translation and cell signalling. Here, we report for the first time that EBNA1 enhances activity of the AP-1 transcription factor in NPC cells and demonstrate that this is achieved by EBNA1 binding to the promoters of c-Jun and ATF2, enhancing their expression. In addition, we demonstrate elevated expression of the AP-1 targets interleukin 8, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 in response to EBNA1 expression, which enhances microtubule formation in an angiogenesis assay. Furthermore, we confirm elevation of VEGF and the phosphorylated isoforms of c-Jun and ATF2 in NPC biopsies. These findings implicate EBNA1 in the angiogenic process and suggest that this viral protein might directly contribute to the development and aggressively metastatic nature of NPC.

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2008-11-01
2019-11-19
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References

  1. Ahn, J. D., Morishita, R., Kaneda, Y., Lee, S. J., Kwon, K. Y., Choi, S. Y., Lee, K. U., Park, J. Y., Moon, I. J. & other authors ( 2002; ). Inhibitory effects of novel AP-1 decoy oligodeoxynucleotides on vascular smooth muscle cell proliferation in vitro and neointimal formation in vivo. Circ Res 90, 1325–1332.[CrossRef]
    [Google Scholar]
  2. An, J., Lichtenstein, A. K., Brent, G. & Rettig, M. B. ( 2002; ). The Kaposi sarcoma-associated herpesvirus (KSHV) induces cellular interleukin 6 expression: role of the KSHV latency-associated nuclear antigen and the AP1 response element. Blood 99, 649–654.[CrossRef]
    [Google Scholar]
  3. Behren, A., Simon, C., Schwab, R. M., Loetzsch, E., Brodbeck, S., Huber, E., Stubenrauch, F., Zenner, H. P. & Iftner, T. ( 2005; ). Papillomavirus E2 protein induces expression of the matrix metalloproteinase-9 via the extracellular signal-regulated kinase/activator protein-1 signaling pathway. Cancer Res 65, 11613–11621.[CrossRef]
    [Google Scholar]
  4. Cai, Q. L., Knight, J. S., Verma, S. C., Zald, P. & Robertson, E. S. ( 2006; ). EC5S ubiquitin complex is recruited by KSHV latent antigen LANA for degradation of the VHL and p53 tumor suppressors. PLOS Pathog 2, e116 [CrossRef]
    [Google Scholar]
  5. Cai, Q., Murakami, M., Si, H. & Robertson, E. S. ( 2007; ). A potential α-helix motif in the amino terminus of LANA encoded by Kaposi's sarcoma-associated herpesesvirus is critical for nuclear accumulation of HIF-1α in normoxia. J Virol 81, 10413–10423.[CrossRef]
    [Google Scholar]
  6. Chan, C. M., Ma, B. B., Hui, E. P., Wong, S. C., Mo, F. K., Leung, S. F., Kam, M. K. & Chan, A. T. ( 2007; ). Cyclooxygenase-2 expression in advanced nasopharyngeal carcinoma – a prognostic evaluation and correlation with hypoxia inducible factor 1α and vascular endothelial growth factor. Oral Oncol 43, 373–378.[CrossRef]
    [Google Scholar]
  7. Chau, C. M. & Lieberman, P. M. ( 2004; ). Dynamic chromatin boundaries delineate a latency control region of Epstein–Barr virus. J Virol 78, 12308–12319.[CrossRef]
    [Google Scholar]
  8. Choi, K. S., Bae, M. K., Jeong, J. W., Moon, H. E. & Kim, K. W. ( 2003; ). Hypoxia-induced angiogenesis during carcinogenesis. J Biochem Mol Biol 36, 120–127.[CrossRef]
    [Google Scholar]
  9. Eferl, R. & Wagner, E. F. ( 2003; ). AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3, 859–868.[CrossRef]
    [Google Scholar]
  10. Eliopoulos, A. G., Stack, M., Dawson, C. W., Kaye, K. M., Hodgkin, L., Sihota, S., Rowe, M. & Young, L. S. ( 1997; ). Epstein–Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-κB pathway involving TNF receptor-associated factors. Oncogene 14, 2899–2916.[CrossRef]
    [Google Scholar]
  11. Eliopoulos, A. G., Gallagher, N. J., Blake, S. M. S., Dawson, C. W. & Young, L. S. ( 1999; ). Activation of the p38 mitogen-activated protein kinase pathway by Epstein–Barr virus-encoded latent membrane protein 1 coregulates interleukin-6 and interleukin-8 production. J Biol Chem 274, 16085–16096.[CrossRef]
    [Google Scholar]
  12. Gokhale, A. S., Haddad, R. I., Cavacini, L. A., Wirth, L., Weeks, L., Hallar, M., Faucher, J. & Posner, M. R. ( 2005; ). Serum concentrations of interleukin-8, vascular endothelial growth factor, and epidermal growth factor receptor in patients with squamous cell cancer of the head and neck. Oral Oncol 41, 70–76.
    [Google Scholar]
  13. Ham, J., Babij, C., Whitfield, J., Pfarr, C. M., Lallemand, D., Yaniv, M. & Rubin, L. L. ( 1995; ). A c-Jun dominant negative mutant protects sympathetic neurons against programmed cell death. Neuron 14, 927–939.[CrossRef]
    [Google Scholar]
  14. Hess, J., Angel, P. & Schorpp-Kistner, M. ( 2004; ). AP-1 subunits: quarrel and harmony among siblings. J Cell Sci 117, 5965–5973.[CrossRef]
    [Google Scholar]
  15. Holowaty, M. N. & Frappier, L. ( 2004; ). HAUSP/USP7 as an Epstein–Barr virus target. Biochem Soc Trans 32, 731–732.[CrossRef]
    [Google Scholar]
  16. Hussain, S. A., Ganesan, R., Reynolds, G., Gross, L., Stevens, A., Pastorek, J., Murray, P. G., Perunovic, B., Anwar, M. S. & other authors ( 2007; ). Hypoxia-regulated carbonic anhydrase IX expression is associated with poor survival in patients with invasive breast cancer. Br J Cancer 96, 104–109.[CrossRef]
    [Google Scholar]
  17. Josko, J. & Mazurek, M. ( 2004; ). Transcription factors having impact on vascular endothelial growth factor (VEGF) gene expression in angiogenesis. Med Sci Monit 10, RA89–RA98.
    [Google Scholar]
  18. Kang, M. S., Hung, S. C. & Kieff, E. ( 2001; ). Epstein–Barr virus nuclear antigen 1 activates transcription from episomal but not integrated DNA and does not alter lymphocyte growth. Proc Natl Acad Sci U S A 98, 15233–15238.[CrossRef]
    [Google Scholar]
  19. Kieff, E. & Rickinson, A. B. ( 2001; ). Epstein–Barr Virus. In Field's Virology, vol. 4, pp. 2511–2574. Edited by D. M. Knipe & P. M Howley. Philadelphia, PA: Lippincott Williams and Wilkins.
  20. Kieser, A., Kilger, E., Gires, O., Ueffing, M., Kolch, W. & Hammerschmidt, W. ( 1997; ). Epstein–Barr virus latent membrane protein-1 triggers AP-1 activity via the c-Jun N-terminal kinase cascade. EMBO J 16, 6478–6485.[CrossRef]
    [Google Scholar]
  21. Komano, J., Sugiura, M. & Takada, K. ( 1998; ). Epstein–Barr virus contributes to the malignant phenotype and to apoptosis resistance in Burkitt's lymphoma cell line Akata. J Virol 72, 9150–9156.
    [Google Scholar]
  22. Krishna, S. M., James, S. & Balaram, P. ( 2006; ). Expression of VEGF as prognosticator in primary nasopharyngeal cancer and its relation to EBV status. Virus Res 115, 85–90.[CrossRef]
    [Google Scholar]
  23. Kube, D., Vockerodt, M., Weber, O., Hell, K., Wolf, J., Haier, B., Grässer, F. A., Müller-Lantzsch, N., Kieff, E. & other authors ( 1999; ). Expression of Epstein–Barr virus nuclear antigen 1 is associated with enhanced expression of CD25 in the Hodgkin cell line L428. J Virol 73, 1630–1636.
    [Google Scholar]
  24. Ludwig, S., Planz, O., Pleschka, S. & Wolff, T. ( 2003; ). Influenza-virus-induced signalling cascades: targets for antiviral therapy? Trends Mol Med 9, 46–52.[CrossRef]
    [Google Scholar]
  25. Ma, J., Zhang, L., Ru, G. Q., Zhao, Z. S. & Xu, W. F. ( 2007; ). Upregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma. World J Gastroenterol 13, 1680–1686.[CrossRef]
    [Google Scholar]
  26. Marechal, V., Dehee, A., Chikhi-Brachet, R., Piolot, T., Coppey-Moisan, M. & Nicolas, J. ( 1999; ). Mapping EBNA-1 domains involved in binding to metaphase chromosomes. J Virol 73, 4385–4392.
    [Google Scholar]
  27. Minet, E., Ernest, I., Michel, G., Remacle, R. J., Raes, M. & Michiels, C. ( 1999; ). HIF1α gene transcription is dependent on a core promoter sequence encompassing activating and inhibiting sequences located upstream from the transcription initiation site and cis elements located within the 5′UTR. Biochem Biophys Res Commun 261, 534–540.[CrossRef]
    [Google Scholar]
  28. Panteva, M., Korkaya, H. & Jameel, S. ( 2003; ). Hepatitis viruses and the MAPK pathway: is this a survival strategy? Virus Res 92, 131–140.[CrossRef]
    [Google Scholar]
  29. Qian, C. N., Zhang, C., Guo, X., Hong, M. H., Cao, S. M., Mai, W. Y., Min, H. Q. & Zeng, Y. X. ( 2000; ). Elevation of serum vascular endothelial growth factor in male patients with metastatic nasopharyngeal carcinoma. Cancer 88, 255–261.[CrossRef]
    [Google Scholar]
  30. Raab-Traub, N. ( 2002; ). Epstein–Barr virus in the pathogenesis of NPC. Semin Cancer Biol 12, 431–441.[CrossRef]
    [Google Scholar]
  31. Ruf, I. K., Rhyne, P. W., Yang, C., Cleveland, J. L. & Sample, J. T. ( 2000; ). Epstein–Barr virus small RNAs potentiate tumorigenicity of Burkitt lymphoma cells independently of an effect on apoptosis. J Virol 74, 10223–10228.[CrossRef]
    [Google Scholar]
  32. Salceda, S. & Caro, J. ( 1997; ). Hypoxia-inducible factor 1α (HIF-1α) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 272, 22642–22647.[CrossRef]
    [Google Scholar]
  33. Sample, J., Henson, E. B. & Sample, C. ( 1992; ). The Epstein–Barr virus nuclear protein 1 promoter active in type I latency is autoregulated. J Virol 66, 4654–4661.
    [Google Scholar]
  34. Shaulian, E. & Karin, M. ( 2002; ). AP-1 as a regulator of cell life and death. Nat Cell Biol 4, E131–E136.[CrossRef]
    [Google Scholar]
  35. Srinivas, S. K. & Sixbey, J. W. ( 1995; ). Epstein–Barr virus induction of recombinase-activating genes RAG1 and RAG2. J Virol 69, 8155–8158.
    [Google Scholar]
  36. Tsai, C. L., Li, H. P., Lu, Y. J., Hsueh, C., Liang, Y., Chen, C. L., Tsao, S. W., Tse, K. P., Yu, J. S. & Chang, Y. S. ( 2006; ). Activation of DNA methyltransferase 1 by EBV LMP1 involves c-Jun NH2-terminal kinase signaling. Cancer Res 66, 11668–11676.[CrossRef]
    [Google Scholar]
  37. Tyler, K. L., Clarke, O., DeBiasi, R. L., Kominsky, D. & Poggioli, G. ( 2001; ). Reoviruses and the host cell. Trends Microbiol 9, 560–564.[CrossRef]
    [Google Scholar]
  38. Vadigepalli, R., Chakravarthula, P., Zak, D. E., Schwaber, J. S. & Gonye, G. E. ( 2003; ). paint: a promoter analysis and interaction network generation tool for gene regulatory network identification. OMICS 7, 235–252.[CrossRef]
    [Google Scholar]
  39. Wakisaka, N. & Pagano, J. S. ( 2003; ). Epstein–Barr virus induces invasion and metastasis factors. Anticancer Res 23 (3A), 2133–2138.
    [Google Scholar]
  40. Wakisaka, N., Kondo, S., Yoshizaki, T., Murono, S., Furukawa, M. & Pagano, J. S. ( 2004; ). Epstein–Barr virus latent membrane protein 1 induces synthesis of hypoxia-inducible factor 1α. Mol Cell Biol 24, 5223–5234.[CrossRef]
    [Google Scholar]
  41. Wei, P., Inamdar, N. & Vedeckis, W. V. ( 1998; ). Transrepression of c-Jun gene expression by the glucocorticoid receptor requires both AP-1 sites in the c-Jun promoter. Mol Endocrinol 12, 1322–1333.[CrossRef]
    [Google Scholar]
  42. Wilson, J. B., Bell, J. L. & Levine, A. J. ( 1996; ). Expression of Epstein–Barr virus nuclear antigen-1 induces B cell neoplasia in transgenic mice. EMBO J 15, 3117–3126.
    [Google Scholar]
  43. Wood, V. H. J., O'Neil, J. D., Wei, W., Stewart, S. E., Dawson, C. W. & Young, L. S. ( 2007; ). Epstein–Barr virus-encoded EBNA1 regulates cellular gene transcription and modulates the STAT1 and TGFβ signalling pathways. Oncogene 26, 4135–4147.[CrossRef]
    [Google Scholar]
  44. Yoshizaki, T., Horikawa, T., Qin-Chun, R., Wakisaka, N., Takeshita, H., Sheen, T. S., Lee, S. Y., Sato, H. & Furukawa, M. ( 2001; ). Induction of interleukin-8 by Epstein–Barr virus latent membrane protein-1 and its correlation to angiogenesis in nasopharyngeal carcinoma. Clin Cancer Res 7, 1946–1951.
    [Google Scholar]
  45. Young, L. S. & Rickinson, A. B. ( 2004; ). Epstein-Barr virus: 40 years on. Nat Rev Cancer 4, 757–768.[CrossRef]
    [Google Scholar]
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