Skip to main content

Advertisement

SpringerLink
Log in

Investigation on the association between thyroid tumorigeneses and herpesviruses

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Herpesviruses have been associated with various human malignancies and with thyroid autoimmunity. Aiming to investigate the presence of these viruses in thyroid nodules, we analyzed serum and thyroid tissue from 183 patients (83 benign and 100 malignant thyroid nodules). We also obtained 104 normal thyroid tissues extracted from the contralateral lobe of these patients. We used ELISA to screen the serology of all patients and a real-time quantitative PCR to analyze thyroid tissue viral load in antibody-positive patients. In addition, the presence of herpesviruses was tested by histological analysis in 20 EBV-positive tissues using the expression of LMP-1 by immunohistochemistry (IHC) and EBER by in situ hybridization (ISH). There was no evidence of HSV-2 or CMV DNA, but we found EBV DNA sequences in 29 (16%) thyroid tissue samples. We also found 7 positive EBV cases out of 104 normal tissues. Viral load was higher in tumors than in their respective normal tissues (p = 0.0002). ISH analysis revealed EBER expression in 11 out of 20 (52%) EBV-positive tissues, mostly in malignant cases (8/11, 73%). The presence of high EBV copy numbers in thyroid tumors and the expression of EBER only in malignant cases suggest an association between EBV and thyroid malignancies. However, we did not find any association between the presence of EBV and/or its viral load and any clinical or pathological tumor feature. Further studies aiming to clarify the mechanisms of EBV infection in thyroid cells are necessary to support a possible role in the development of thyroid cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Morrison BJ, Labo N, Miley WJ, Whitby D (2015) Serodiagnosis for tumor viruses. Semin Oncol 42(2):191–206. doi:10.1053/j.seminoncol.2014.12.024

    Article  PubMed  Google Scholar 

  2. Frappier L (2013) A cancer-associated Epstein-Barr virus variant with epithelial tropism. Trends Microbiol 21(12):616–617. doi:10.1016/j.tim.2013.10.007

    Article  CAS  PubMed  Google Scholar 

  3. Tsai MH, Raykova A, Klinke O, Bernhardt K, Gartner K, Leung CS, Geletneky K, Sertel S, Munz C, Feederle R, Delecluse HJ (2013) Spontaneous lytic replication and epitheliotropism define an Epstein-Barr virus strain found in carcinomas. Cell reports 5(2):458–470. doi:10.1016/j.celrep.2013.09.012

    Article  CAS  PubMed  Google Scholar 

  4. Tsao SW, Tsang CM, To KF, Lo KW (2015) The role of Epstein-Barr virus in epithelial malignancies. J Pathol 235(2):323–333. doi:10.1002/path.4448

    Article  CAS  PubMed  Google Scholar 

  5. Kieff ER, A. B (2001) Fields virology. Lippincott Williams and Wilkins, Philadelphia

    Google Scholar 

  6. Saha A, Robertson ES (2011) Epstein-Barr virus-associated B-cell lymphomas: pathogenesis and clinical outcomes. Clin Cancer Res Off J Am Assoc Cancer Res 17(10):3056–3063. doi:10.1158/1078-0432.CCR-10-2578

    Article  CAS  Google Scholar 

  7. Thompson MP, Kurzrock R (2004) Epstein-Barr virus and cancer. Clin Cancer Res Off J Am Assoc Cancer Res 10(3):803–821

    Article  CAS  Google Scholar 

  8. Rasul AE, Nagy N, Sohlberg E, Adori M, Claesson HE, Klein G, Klein E (2012) Simultaneous detection of the two main proliferation driving EBV encoded proteins, EBNA-2 and LMP-1 in single B cells. J Immunol Methods 385(1–2):60–70. doi:10.1016/j.jim.2012.08.008

    Article  CAS  PubMed  Google Scholar 

  9. Tse E, Kwong YL (2015) Epstein Barr virus-associated lymphoproliferative diseases: the virus as a therapeutic target. Exp Mol Med 47:e136. doi:10.1038/emm.2014.102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Vockerodt M, Yap LF, Shannon-Lowe C, Curley H, Wei W, Vrzalikova K, Murray PG (2015) The Epstein-Barr virus and the pathogenesis of lymphoma. J Pathol 235(2):312–322. doi:10.1002/path.4459

    Article  PubMed  Google Scholar 

  11. Herbert KM, Pimienta G (2016) Consideration of Epstein-Barr Virus-Encoded Noncoding RNAs EBER1 and EBER2 as a Functional Backup of Viral Oncoprotein Latent Membrane Protein 1. mBio 7(1):e01926–01915. doi:10.1128/mBio.01926-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ito Y, Kawamura Y, Iwata S, Kawada J, Yoshikawa T, Kimura H (2013) Demonstration of type II latency in T lymphocytes of Epstein-Barr Virus-associated hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 60(2):326–328. doi:10.1002/pbc.24319

    Article  PubMed  Google Scholar 

  13. Klein E, Nagy N, Rasul AE (2013) EBV genome carrying B lymphocytes that express the nuclear protein EBNA-2 but not LMP-1: Type IIb latency. Oncoimmunology 2(2):e23035. doi:10.4161/onci.23035

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zhao J, Jin H, Cheung KF, Tong JH, Zhang S, Go MY, Tian L, Kang W, Leung PP, Zeng Z, Li X, To KF, Sung JJ, Yu J (2012) Zinc finger E-box binding factor 1 plays a central role in regulating Epstein-Barr virus (EBV) latent-lytic switch and acts as a therapeutic target in EBV-associated gastric cancer. Cancer 118(4):924–936. doi:10.1002/cncr.26184

    Article  CAS  PubMed  Google Scholar 

  15. Leite JL, Bufalo NE, Santos RB, Romaldini JH, Ward LS (2010) Herpesvirus type 7 infection may play an important role in individuals with a genetic profile of susceptibility to Graves’ disease. Eur J Endocrinol Eur Fed Endoc Soc 162(2):315–321. doi:10.1530/EJE-09-0719

    Article  CAS  Google Scholar 

  16. Leite JL, Manfrinatto JA, Mazzali M, Ward LS (2006) Polymorphisms at exon 4 of p53 and the susceptibility to herpesvirus types 6 and 1 infection in renal transplant recipients. Transpl Int Off J Eur Soc Organ Transpl 19(9):732–737. doi:10.1111/j.1432-2277.2006.00346.x

    CAS  Google Scholar 

  17. Nagata K, Fukata S, Kanai K, Satoh Y, Segawa T, Kuwamoto S, Sugihara H, Kato M, Murakami I, Hayashi K, Sairenji T (2011) The influence of Epstein-Barr virus reactivation in patients with Graves’ disease. Viral Immunol 24(2):143–149. doi:10.1089/vim.2010.0072

    Article  CAS  PubMed  Google Scholar 

  18. Thomas D, Karachaliou F, Kallergi K, Vlachopapadopoulou E, Antonaki G, Chatzimarkou F, Fotinou A, Kaldrymides P, Michalacos S (2008) Herpes virus antibodies seroprevalence in children with autoimmune thyroid disease. Endocr 33(2):171–175. doi:10.1007/s12020-008-9068-8

    Article  CAS  Google Scholar 

  19. Griffiths P, Baraniak I, Reeves M (2015) The pathogenesis of human cytomegalovirus. J Pathol 235(2):288–297. doi:10.1002/path.4437

    Article  CAS  PubMed  Google Scholar 

  20. Greene FL, Sobin LH (2002) The TNM system: our language for cancer care. J Surg Oncol 80(3):119–120. doi:10.1002/jso.10114

    Article  PubMed  Google Scholar 

  21. Aryee EA, Bailey RL, Natividad-Sancho A, Kaye S, Holland MJ (2005) Detection, quantification and genotyping of Herpes Simplex Virus in cervicovaginal secretions by real-time PCR: a cross sectional survey. Virol J 2:61. doi:10.1186/1743-422X-2-61

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kim do N, Seo MK, Choi H, Kim SY, Shin HJ, Yoon AR, Tao Q, Rha SY, Lee SK (2013) Characterization of naturally Epstein-Barr virus-infected gastric carcinoma cell line YCCEL1. J Gen Virol 94(Pt 3):497–506. doi:10.1099/vir.0.045237-0

    Article  PubMed  Google Scholar 

  23. Ryan JL, Fan H, Glaser SL, Schichman SA, Raab-Traub N, Gulley ML (2004) Epstein-Barr virus quantitation by real-time PCR targeting multiple gene segments: a novel approach to screen for the virus in paraffin-embedded tissue and plasma. JMD 6(4):378–385. doi:10.1016/S1525-1578(10)60535-1

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Yamamoto T, Yamada A, Tsuji K, Iwatsuki K (2008) Tracing of the molecular remnants of herpes virus infections in necrotic skin tissue. EJD 18(5):499–503. doi:10.1684/ejd.2008.0503

    CAS  PubMed  Google Scholar 

  25. Rowe DT, Webber S, Schauer EM, Reyes J, Green M (2001) Epstein-Barr virus load monitoring: its role in the prevention and management of post-transplant lymphoproliferative disease. Transpl Infect Dis Off J Transpl Soc 3(2):79–87

    Article  CAS  Google Scholar 

  26. Weinstock DM, Ambrossi GG, Brennan C, Kiehn TE, Jakubowski A (2006) Preemptive diagnosis and treatment of Epstein-Barr virus-associated post transplant lymphoproliferative disorder after hematopoietic stem cell transplant: an approach in development. Bone Marrow Transpl 37(6):539–546. doi:10.1038/sj.bmt.1705289

    Article  CAS  Google Scholar 

  27. Martins MB, Marcello MA, Morari EC, Cunha LL, Soares FA, Vassallo J, Ward LS (2013) Clinical utility of KAP-1 expression in thyroid lesions. Endocr Pathol 24(2):77–82. doi:10.1007/s12022-013-9245-z

    Article  CAS  PubMed  Google Scholar 

  28. Gulley ML, Glaser SL, Craig FE, Borowitz M, Mann RB, Shema SJ, Ambinder RF (2002) Guidelines for interpreting EBER in situ hybridization and LMP1 immunohistochemical tests for detecting Epstein-Barr virus in Hodgkin lymphoma. Am J Clin Pathol 117(2):259–267. doi:10.1309/MMAU-0QYH-7BHA-W8C2

    Article  PubMed  Google Scholar 

  29. Clemens SA, Farhat CK (2010) Seroprevalence of herpes simplex 1–2 antibodies in Brazil. Rev Saude Publica 44(4):726–734

    Article  PubMed  Google Scholar 

  30. Hadinoto V, Shapiro M, Greenough TC, Sullivan JL, Luzuriaga K, Thorley-Lawson DA (2008) On the dynamics of acute EBV infection and the pathogenesis of infectious mononucleosis. Blood 111(3):1420–1427. doi:10.1182/blood-2007-06-093278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Souza MA, Passos AM, Treitinger A, Spada C (2010) Seroprevalence of cytomegalovirus antibodies in blood donors in southern, Brazil. Rev Soc Bras Med Trop 43(4):359–361

    Article  PubMed  Google Scholar 

  32. Chan KH, Gu YL, Ng F, Ng PS, Seto WH, Sham JS, Chua D, Wei W, Chen YL, Luk W, Zong YS, Ng MH (2003) EBV specific antibody-based and DNA-based assays in serologic diagnosis of nasopharyngeal carcinoma. Int J Cancer Journal international du cancer 105(5):706–709. doi:10.1002/ijc.11130

    Article  CAS  PubMed  Google Scholar 

  33. Fan H, Nicholls J, Chua D, Chan KH, Sham J, Lee S, Gulley ML (2004) Laboratory markers of tumor burden in nasopharyngeal carcinoma: a comparison of viral load and serologic tests for Epstein-Barr virus. Int J Cancer Journal international du cancer 112(6):1036–1041. doi:10.1002/ijc.20520

    Article  CAS  PubMed  Google Scholar 

  34. Gulley ML, Tang W (2008) Laboratory assays for Epstein-Barr virus-related disease. JMD 10(4):279–292. doi:10.2353/jmoldx.2008.080023

    PubMed  PubMed Central  Google Scholar 

  35. Paramita DK, Fachiroh J, Artama WT, van Benthem E, Haryana SM, Middeldorp JM (2007) Native early antigen of Epstein-Barr virus, a promising antigen for diagnosis of nasopharyngeal carcinoma. J Med Virol 79(11):1710–1721. doi:10.1002/jmv.20987

    Article  CAS  PubMed  Google Scholar 

  36. Jensen K, Patel A, Larin A, Hoperia V, Saji M, Bauer A, Yim K, Hemming V, Vasko V (2010) Human herpes simplex viruses in benign and malignant thyroid tumours. J Pathol 221(2):193–200. doi:10.1002/path.2701

    Article  CAS  PubMed  Google Scholar 

  37. Tsai JH, Tsai CH, Cheng MH, Lin SJ, Xu FL, Yang CC (2005) Association of viral factors with non-familial breast cancer in Taiwan by comparison with non-cancerous, fibroadenoma, and thyroid tumor tissues. J Med Virol 75(2):276–281. doi:10.1002/jmv.20267

    Article  PubMed  Google Scholar 

  38. Stamatiou D, Derdas SP, Symvoulakis EK, Sakorafas GH, Zoras O, Spandidos DA (2015) Investigation of BK virus, Epstein-Barr virus and human papillomavirus sequences in postoperative thyroid gland specimens. Int J Biol Mark 30(1):e104–e110. doi:10.5301/jbm.5000115

    Google Scholar 

  39. Yin Y, Manoury B, Fahraeus R (2003) Self-inhibition of synthesis and antigen presentation by Epstein-Barr virus-encoded EBNA1. Science 301(5638):1371–1374. doi:10.1126/science.1088902

    Article  CAS  PubMed  Google Scholar 

  40. Ma L, Deng X, Wu M, Zhang G, Huang J (2014) Down-regulation of miRNA-204 by LMP-1 enhances CDC42 activity and facilitates invasion of EBV-associated nasopharyngeal carcinoma cells. FEBS Lett 588(9):1562–1570. doi:10.1016/j.febslet.2014.02.039

    Article  CAS  PubMed  Google Scholar 

  41. Rosales-Perez S, Cano-Valdez AM, Flores-Balcazar CH, Guedea-Edo F, Lino-Silva LS, Lozano-Borbalas A, Navarro-Martin A, Poitevin-Chacon A (2014) Expression of Epstein-Barr virus-encoded latent membrane protein (LMP-1), p16 and p53 proteins in nonendemic nasopharyngeal carcinoma (NPC): a clinicopathological study. Arch Med Res 45(3):229–236. doi:10.1016/j.arcmed.2014.02.002

    Article  CAS  PubMed  Google Scholar 

  42. Lassmann H, Niedobitek G, Aloisi F, Middeldorp JM, NeuroproMiSe EBVWG (2011) Epstein-Barr virus in the multiple sclerosis brain: a controversial issue–report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria. Brain J Neurol 134(Pt 9):2772–2786. doi:10.1093/brain/awr197

    Article  Google Scholar 

  43. Klumb CE, Hassan R, De Oliveira DE, De Resende LM, Carrico MK, De Almeida Dobbin J, Pombo-De-Oliveira MS, Bacchi CE, Maia RC (2004) Geographic variation in Epstein-Barr virus-associated Burkitt’s lymphoma in children from Brazil. Int J Cancer Journal international du cancer 108(1):66–70. doi:10.1002/ijc.11443

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the excellent text revision of Etna Macário (Faculty of Medical Sciences). A special thanks to our group from the Laboratory of Cancer Molecular Genetics (GEMOCA) and to Dr. Cláudio Pannuti and Dr. Renato dos Reis Oliveira from the Laboratory of Virology, São Paulo Institute of Tropical Medicine, University of São Paulo, School of Medicine for their valuable contribution to the experimental design of this work.

Author information

Authors and Affiliations

  1. Laboratory of Cancer Molecular Genetics (Gemoca), Faculty of Medical Sciences, University of Campinas (FCM-Unicamp), Tessália Vieira de Camargo Street, 126, Cidade Universitária, Campinas, São Paulo, 13083-887, Brazil

    J. F. M. Almeida, M. A. Marcello, N. E. Bufalo, L. H. P. Amaral, A. B. Marques, L. L. Cunha, P. C. Tincani & L. S. Ward

  2. Department of Anatomic Pathology, AC Camargo Cancer Center, Taguá Street, 440, Liberdade, São Paulo, SP, 01508-010, Brazil

    A. H. Campos

  3. Clinical Pathology Department, Faculty of Medical Sciences, University of Campinas (FCM-Unicamp), Vital Brasil Street, 251, Cidade Universitária, Campinas, São Paulo, 13083-888, Brazil

    C. L. Rossi

  4. Laboratory of Pathology, Clinical Pathology Institute (IPC), Av. Orosimbo Maia, 165, Vila Itapura, Campinas, São Paulo, 13023-002, Brazil

    C. A. Alvarenga

  5. Head and Neck Surgery Department, University of Campinas Teaching Hospital (HC-Unicamp), Vital Brasil Street, 251, Cidade Universitária, Campinas, SP, 13083-888, Brazil

    A. J. Tincani

Authors
  1. J. F. M. Almeida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. H. Campos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. A. Marcello
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N. E. Bufalo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. L. Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L. H. P. Amaral
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. B. Marques
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L. L. Cunha
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C. A. Alvarenga
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. P. C. Tincani
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A. J. Tincani
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. L. S. Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L. S. Ward.

Ethics declarations

Conflict of interest

None of the authors have any potential conflicts of interest. This study received financial support from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Grant #2012/09625-0.

Ethical standard

This study was approved by our institutional ethics committee (Number 982/2011). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Almeida, J.F.M., Campos, A.H., Marcello, M.A. et al. Investigation on the association between thyroid tumorigeneses and herpesviruses. J Endocrinol Invest 40, 823–829 (2017). https://doi.org/10.1007/s40618-017-0609-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-017-0609-y

Keywords

Search

Navigation