Medical Oncology

, Volume 22, Issue 2, pp 113–121

Involvement of the epstein-barr virus in the nasopharyngeal carcinoma pathogenesis

Review

Abstract

The aim of this study was to discuss the relevance of the Epstein-Barr virus (EBV) in the nasopharyngeal carcinoma (NPC), analyzing the variations of several molecules potentially involved in the pathogenesis of this cancer. EBV was detected in all the NPC samples by several techniques including PCR, in situ hybridization, and immunohistochemical methodologies. CD21 membrane receptor was absent after EBV infection, being a differential morphological feature of the tumoral cells. Latent membrane protein-1 (LMP1), an oncogenic viral product, was detected in a high percentage of samples, supporting a role for EBV in the pathogenesis of NPC. Bcl-2, an anti-apoptotic protein up-regulated by LMP1, was also overexpressed, coinciding with the majority of samples positive for LMP1. Finally, p53 presented abnormalities only in a low percentage of samples. These results reinforce the role of the EBV in the NPC discussing several potential mechanisms of pathogenesis in this neoplasia.

Key Words

Epstein-Barr virus nasopharyngeal carcinoma CD21 EBER LMP1 Bcl-2 p53 

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References

  1. 1.
    Liebowitz D. Nasopharyngeal carcinoma: the Epstein-Barr virus association. Semin Oncol 1994; 21:376–381.PubMedGoogle Scholar
  2. 2.
    Borza CM, Hutt-Fletcher LM. Alternate replication in B cells and epithelial cells switches tropism of Epstein-Barr virus. Nat Med 2002; 8:594–599.PubMedCrossRefGoogle Scholar
  3. 3.
    Niedobitek G, Young LS. Epstein-Barr virus persistence and virus-associated tumours. Lancet 1994; 343:333–335.PubMedCrossRefGoogle Scholar
  4. 4.
    Pathmanathan R, Prasad U, Sadler R, Flynn K, Raab-Traub N. Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N Engl J Med 1995; 333:693–698.PubMedCrossRefGoogle Scholar
  5. 5.
    Epstein MA, Barr YM, Achong BG. Preliminary observations on new lymphoblast strains (EB4, EB5) from Burkitt tumours in a British and a Ugandan patient. Br J Cancer 1966; 20:475–479.PubMedCrossRefGoogle Scholar
  6. 6.
    Shanmugaratnam K, Sobin LH. The World Health Organization histological classification of tumours of the upper respiratory tract and ear. A commentary on the second edition. Cancer 1993; 71:2689–2697.PubMedCrossRefGoogle Scholar
  7. 7.
    Fingeroth JD, Diamond ME, Sage DR, Hayman J, Yates JL. CD21-dependent infection of an epithelial cell line, 293, by Epstein-Barr virus. J Virol 1999; 73:2115–2125.PubMedGoogle Scholar
  8. 8.
    Imai S, Nishikawa J, Takada K. Cell-to-cell contact as an efficient mode of Epstein-Barr virus infection of diverse human epithelial cells. J Virol 1998; 72:4371–4378.PubMedGoogle Scholar
  9. 9.
    Vera-Sempere F, Burgos J, Botella MS, Morera C. Comparative analysis of Epstein-Barr virus (EBV) detection by nested-PCR and non-isotopic in situ hybridization in nasopharyngeal carcinoma (NPC). Clin Chim Acta 1998; 271:119–132.PubMedCrossRefGoogle Scholar
  10. 10.
    Vera-Sempere FJ, Burgos JS, Botella MS, Cordoba J, Gobernado M. Immunohistochemical expression of Epstein-Barr virus-encoded latent membrane protein (LMP-1) in paraffin sections of EBV-associated nasopharyngeal carcinoma in Spanish patients. Eur J Cancer B Oral Oncol 1996; 32B:163–168.PubMedCrossRefGoogle Scholar
  11. 11.
    Burgos JS, Vera-Sempere FJ. Analysis of EBV latency by EBER in situ hybridization in nasopharyngeal carcinoma Spanish patients. Anticancer Res 2001; 21:3921–3924.PubMedGoogle Scholar
  12. 12.
    Fingeroth JD, Weis JJ, Tedder TF, Strominger JL, Biro PA, Fearon DT. Epstein-Barr virus receptor of human B lymphocytes is the C3d receptor CR2. Proc Natl Acad Sci USA 1984; 81:4510–4514.PubMedCrossRefGoogle Scholar
  13. 13.
    Young LS, Clark D, Sixbey JW, Rickinson AB. Epstein-Barr virus receptors on human pharyngeal epithelia. Lancet 1986; 1:240–242.PubMedCrossRefGoogle Scholar
  14. 14.
    Birkenbach M, Tong X, Bradbury LE, Tedder TF, Kieff E. Characterization of an Epstein-Barr virus receptor on human epithelial cells. J Exp Med 1992; 176:1405–1414.PubMedCrossRefGoogle Scholar
  15. 15.
    Burgos JS, Vera-Sempere FJ. Immunohistochemical absence of CD21 membrane receptor in nasopharyngeal carcinoma cells infected by Epstein-Barr virus in Spanish patients. Laryngoscope 2000; 110:2081–2084.PubMedCrossRefGoogle Scholar
  16. 16.
    Billaud M, et al. Epstein-Barr virus (EBV)-containing nasopharyngeal carcinoma cells express the B-cell activation antigen blast2/CD23 and low levels of the EBV receptor CR2. J Virol 1989; 63:4121–4128.PubMedGoogle Scholar
  17. 17.
    Busson P, et al. Establishment and characterization of three transplantable EBV-containing nasopharyngeal carcinomas. Int J Cancer 1988; 42:599–606.PubMedCrossRefGoogle Scholar
  18. 18.
    Glickman JN, Howe JG, Steitz JA. Structural analyses of EBER1 and EBER2 ribonucleoprotein particles present in Epstein-Barr virus-infected cells. J Virol 1988; 62:902–911.PubMedGoogle Scholar
  19. 19.
    Wu TC, et al. Abundant expression of EBER1 small nuclear RNA in nasopharyngeal carcinoma. A morphologically distinctive target for detection of Epstein-Barr virus in formalin-fixed paraffin-embedded carcinoma specimens. Am J Pathol 1991; 138:1461–1469.PubMedGoogle Scholar
  20. 20.
    Lerner MR, Andrews NC, Miller G, Steitz JA. Two small RNAs encoded by Epstein-Barr virus and complexed with protein are precipitated by antibodies from patients with systemic lupus erythematosus. Proc Natl Acad Sci USA 1981; 78:805–809.PubMedCrossRefGoogle Scholar
  21. 21.
    Hudson GS, Farrell PJ, Barrell BG. Two related but differentially expressed potential membrane proteins encoded by the EcoRI Dhet region of Epstein-Barr virus B95-8. J Virol 1985; 53:528–535.PubMedGoogle Scholar
  22. 22.
    Wang D, Liebowitz D, Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell 1985; 43:831–840.PubMedCrossRefGoogle Scholar
  23. 23.
    Moorthy RK, Thorley-Lawson DA. All three domains of the Epstein-Barr virus-encoded latent membrane protein LMP-1 are required for transformation of rat-1 fibroblasts. J Virol 1993; 67:1638–1646.PubMedGoogle Scholar
  24. 24.
    Martin JM, Veis D, Korsmeyer SJ, Sugden B. Latent membrane protein of Epstein-Barr virus induces cellular phenotypes independently of expression of Bcl-2. J Virol 1993; 67:5269–5278.PubMedGoogle Scholar
  25. 25.
    Uchida J, et al. Mimicry of CD40 signals by Epstein-Barr virus LMP1 in B lymphocyte responses. Science 1999; 286:300–303.PubMedCrossRefGoogle Scholar
  26. 26.
    Hatzivassiliou E, Mosialos G. Cellular signaling pathways engaged by the Epstein-Barr virus transforming protein LMP1. Front Biosci 2002; 7:d319–329.PubMedCrossRefGoogle Scholar
  27. 27.
    Henderson S, et al. Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell 1991; 65:1107–1115.PubMedCrossRefGoogle Scholar
  28. 28.
    Tsujimoto Y, Gorham J, Cossman J, Jaffe E, Croce CM. The t(14;18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining. Science 1985; 229:1390–1393.PubMedCrossRefGoogle Scholar
  29. 29.
    Cleary ML, Smith SD, Sklar J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 1986; 47:19–28.PubMedCrossRefGoogle Scholar
  30. 30.
    Dawson CW, Eliopoulos AG, Dawson J, Young LS. BHRF1, a viral homologue of the Bcl-2 oncogene, disturbs epithelial cell differentiation. Oncogene 1995; 10:69–77.PubMedGoogle Scholar
  31. 31.
    Korsmeyer SJ. Bcl-2: an antidote to programmed cell death. Cancer Surv 1992; 15:105–118.PubMedGoogle Scholar
  32. 32.
    Vera-Sempere FJ, Burgos JS, Botella MS, Morera C. Immunohistochemical expression of Bcl-2 oncoprotein in EBV-associated nasopharyngeal carcinoma correlated to histological type and survival. Histol Histopathol 1997; 12:9–18.PubMedGoogle Scholar
  33. 33.
    Kouvidou Ch KP, et al. Expression of Bcl-2 and p53 proteins in nasopharyngeal carcinoma. Absence of correlation with the presence of EBV encoded EBER1-2 transcripts and latent membrane protein-1. J Clin Pathol Mol Pathol 1995; 148:M17–22.CrossRefGoogle Scholar
  34. 34.
    Lu QL, Elia G, Lucas S, Thomas JA. Bcl-2 proto-oncogene expression in Epstein-Barr-virus-associated nasopharyngeal carcinoma. Int J Cancer 1993; 53:29–35.PubMedCrossRefGoogle Scholar
  35. 35.
    Lane DP. p53 and human cancers. Br Med Bull 1994; 50:582–599.PubMedGoogle Scholar
  36. 36.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science 1991; 253:49–53.PubMedCrossRefGoogle Scholar
  37. 37.
    Chang F SS, Kurvinen K, Syrjanen K. The p53 tumor suppressor gene as a common cellular target in human carcinogenesis. Am J Gastroenterol 1993; 88:174–186.PubMedGoogle Scholar
  38. 38.
    Niedobitek G, Agathanggelou A, Barber P, Smallman LA, Jones EL, Young LS. P53 overexpression and Epstein-Barr virus infection in undifferentiated and squamous cell nasopharyngeal carcinomas. J Pathol 1993; 170:457–461.PubMedCrossRefGoogle Scholar
  39. 39.
    Maestro R, et al. High frequency of p53 gene alterations associated with protein overexpression in human squamous cell carcinoma of the larynx. Oncogene 1992; 7:1159–1166.PubMedGoogle Scholar
  40. 40.
    Sakai E, Tsuchida N. Most human squamous cell carcinomas in the oral cavity contain mutated p53 tumor-suppressor genes. Oncogene 1992; 7:927–933.PubMedGoogle Scholar
  41. 41.
    Niemhom S, Kitazawa S, Murao S, Kunachak S, Maeda S. Co-expression of p53 and bcl-2 may correlate to the presence of epstein-barr virus genome and the expression of proliferating cell nuclear antigen in nasopharyngeal carcinoma. Cancer Lett 2000; 160:199–208.PubMedCrossRefGoogle Scholar
  42. 42.
    Spruck CH, 3rd, et al. Absence of p53 gene mutations in primary nasopharyngeal carcinomas. Cancer Res 1992; 52:4787–4790.PubMedGoogle Scholar
  43. 43.
    Sun Y, et al. An infrequent point mutation of the p53 gene in human nasopharyngeal carcinoma. Proc Natl Acad Sci USA 1992; 89:6516–6520.PubMedCrossRefGoogle Scholar
  44. 44.
    Nasrin N, Taiba K, Hannan N, Hannan M, al-Sedairy S. A molecular study of EBV DNA and p53 mutations in nasopharyngeal carcinoma of Saudi Arab patients. Cancer Lett 1994; 82:189–198.PubMedCrossRefGoogle Scholar
  45. 45.
    Kouvidou C, et al. P21/waf1 protein expression in nasopharyngeal carcinoma. Comparative study with PCNA, p53 and MDM-2 protein expression. Anticancer Res 1997; 17:2615–2619.PubMedGoogle Scholar
  46. 46.
    Burgos JS. Absence of p53 alterations in nasopharyngeal carcinoma Spanish patients with Epstein-Barr virus infection. Virus Genes 2003; 27:263–268.PubMedCrossRefGoogle Scholar
  47. 47.
    Rubio L, Burgos JS, Lopez-Guerrero JA, Morera C, Vera-Sempere FJ. Expression of p53 protein and tumor angiogenesis as prognostic factors in nasopharyngeal carcinoma patients. Pathol Res Pract 2002; 198:97–102.PubMedCrossRefGoogle Scholar
  48. 48.
    Bhargava V, et al. The association of p53 immunopositivity with tumor proliferation and other prognostic indicators in breast cancer. Mod Pathol 1994; 7:361–368.PubMedGoogle Scholar
  49. 49.
    Hurlimann J, Chaubert P, Benhattar J. p53 Gene alterations and p53 protein accumulation in infiltrating ductal breast carcinomas: correlation between immunohistochemical and molecular biology techniques. Mod Pathol 1994; 7:423–428.PubMedGoogle Scholar
  50. 50.
    Thor AD, et al. Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. J Natl Cancer Inst 1992; 84:845–855.PubMedCrossRefGoogle Scholar
  51. 51.
    Werness BA, Levine AJ, Howley PM. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 1990; 248:76–79.PubMedCrossRefGoogle Scholar
  52. 52.
    Lane DP, Crawford LV. T antigen is bound to a host protein in SV40-transformed cells. Nature 1979; 278:261–263.PubMedCrossRefGoogle Scholar
  53. 53.
    Linzer DI, Levine AJ. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 1979; 17:43–52.PubMedCrossRefGoogle Scholar
  54. 54.
    Old LJ BE, Oettgen HF, dé-Harven E, Geering G, Williamson B. Precipitating antibody in human serum to an antigen present in cultured Burkitt’s lymphoma cells. Proc Natl Acad Sci USA 1966; 56:1699–1704.PubMedCrossRefGoogle Scholar
  55. 55.
    Nonoyama M, Huang CH, Pagano JS, Klein G, Singh S. DNA of Epstein-Barr virus detected in tissue of Burkitt’s lymphoma and nasopharyngeal carcinoma. Proc Natl Acad Sci USA 1973; 70:3265–3268.PubMedCrossRefGoogle Scholar
  56. 56.
    Wolf H, zur Hausen H, Becker V. EB viral genomes in epithelial nasopharyngeal carcinoma cells. Nat New Biol 1973; 244:245–247.PubMedGoogle Scholar
  57. 57.
    Klein G, Giovanella BC, Lindahl T, Fialkow PJ, Singh S, Stehlin JS. Direct evidence for the presence of Epstein-Barr virus DNA and nuclear antigen in malignant epithelial cells from patients with poorly differentiated carcinoma of the nasopharynx. Proc Natl Acad Sci USA 1974; 71:4737–4741.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2005

Authors and Affiliations

  1. 1.Centro de Biología Molecular “Severo Ochoa” - C.S.I.C., Facultad de Ciencias, CX Lab. 340Universidad Autónoma de Madrid, CantoblancoMadridSpain

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