O6-methylguanine-DNA methyltransferase in equine sarcoids: molecular and epigenetic analysis

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• 作者：Gennaro Altamura (1)
  Maria Strazzullo (2)
  Annunziata Corteggio (1)
  Romina Francioso (3)
  Franco Roperto (1)
  Maurizio D’Esposito (3) (4)
  Giuseppe Borzacchiello (1)
  
• 关键词：BPV ; Equine sarcoid ; MGMT
• 刊名：BMC Veterinary Research
• 出版年：2012
• 出版时间：December 2012
• 年：2012
• 卷：8
• 期：1
• 全文大小：1098KB
• 参考文献：1. Nasir L, Campo MS: Bovine papillomaviruses: their role in the aetiology of cutaneous tumours of bovids and equids. / Vet Dermatol 2008, 19:243-54. CrossRef
  2. Pilsworth RC, Knottenbelt D: Equine sarcoid. / Equine Vet Educ 2007, 19:260-62. CrossRef
  3. Martens A, De Moor A, Demeulemeester J, Ducatelle R: Histopathological characteristics of five clinical types of equine sarcoid. / Res Vet Sci 2000, 69:295-00. CrossRef
  4. Borzacchiello G, Corteggio A: Equine Sarcoid: State of the Art. / Ippologia 2009, 20:7-4.
  5. Corteggio A, Di Geronimo O, Roperto S, Roperto F, Borzacchiello G: Bovine papillomavirus E7 oncoprotein binds to p600 in naturally occurring equine sarcoids. / J Gen Virol 2011, 92:378-82. CrossRef
  6. Borzacchiello G, Russo V, Della Salda L, Roperto S, Roperto F: Expression of platelet-derived growth factor-beta receptor and bovine papillomavirus E5 and E7 oncoproteins in equine sarcoid. / J Comp Pathol 2008, 139:231-37. CrossRef
  7. Yuan Z, Gault EA, Campo MS, Nasir L: Different contribution of bovine papillomavirus type 1 oncoproteins to the transformation of equine fibroblasts. / J General Virol 2011, 92:773-83. CrossRef
  8. Nixon C, Chambers G, Ellsmore V, Campo MS, Burr P, Argyle DJ, Reid SW, Nasir L: Expression of cell cycle associated proteins cyclin A, CDK-2, p27kip1 and p53 in equine sarcoids. / Cancer Lett 2005, 221:237-45. CrossRef
  9. Pegg AE, Dolan ME, Moschel RC: Structure, function, and inhibition of O6-alkylguanine-DNA alkyltransferase. / Prog Nucleic Acid Res Mol Biol 1995, 51:167-23. CrossRef
  10. Coulondre C, Miller JH: Genetic studies of the lac repressor. IV. Mutagenic specificity in the lacI gene of Escherichia coli. / J Mol Biol 1977, 117:577-06. CrossRef
  11. Erickson LC, Laurent G, Sharkey NA, Kohn KW: DNA cross-linking and monoadduct repair in nitrosourea-treated human tumour cells. / Nature 1980, 288:727-29. CrossRef
  12. Pegg AE: Mammalian O6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. / Cancer Res 1990, 50:6119-129.
  13. Srivenugopal KS, Ali-Osman F: The DNA repair protein, O(6)-methylguanine-DNA methyltransferase is a proteolytic target for the E6 human papillomavirus oncoprotein. / Oncogene 2002, 21:5940-945. CrossRef
  14. Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG: Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. / Cancer Res 1999, 59:793-97.
  15. Esteller M, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Watkins DN, Issa JP, Sidransky D, Baylin SB, Herman JG: Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. / Cancer Res 2000, 60:2368-371.
  16. Henken FE, Wilting SM, Overmeer RM, van Rietschoten JG, Nygren AO, Errami A, Schouten JP, Meijer CJ, Snijders PJ, Steenbergen RD: Sequential gene promoter methylation during HPV-induced cervical carcinogenesis. / Br J Cancer 2007, 97:1457-464. CrossRef
  17. Virmani AK, Muller C, Rathi A, Zoechbauer-Mueller S, Mathis M, Gazdar AF: Aberrant methylation during cervical carcinogenesis. / Clin Cancer Res 2001, 7:584-89.
  18. Herfarth KK, Brent TP, Danam RP, Remack JS, Kodner IJ, Wells SA Jr, Goodfellow PJ: A specific CpG methylation pattern of the MGMT promoter region associated with reduced MGMT expression in primary colorectal cancers. / Mol Carcinog 1999, 24:90-8. CrossRef
  19. Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP: Alterations in DNA methylation: a fundamental aspect of neoplasia. / Adv Cancer Res 1998, 72:141-96. CrossRef
  20. Costello JF, Fruhwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X, Wright FA, Feramisco JD, Peltomaki P, Lang JC, / et al.: Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. / Nat Genet 2000, 24:132-38. CrossRef
  21. Jones PA, Laird PW: Cancer epigenetics comes of age. / Nat Genet 1999, 21:163-67. CrossRef
  22. Baylin SB, Herman JG: DNA hypermethylation in tumorigenesis: epigenetics joins genetics. / Trends Genet 2000, 16:168-74. CrossRef
  23. Sun LL, Cao DY, Yang JX, Li H, Zhou XR, Song ZQ, Cheng XM, Chen J, Shen K: Population-based case–control study on DAPK1, RAR-beta2 and MGMT methylation in liquid-based cytology. / Arch Gynecol Obstet 2012, 285:1433-439. CrossRef
  24. Spathis A, Aga E, Alepaki M, Chranioti A, Meristoudis C, Panayiotides I, Kassanos D, Karakitsos P: Promoter methylation of p16(INK4A), hMLH1, and MGMT in liquid-based cervical cytology samples compared with clinicopathological findings and HPV presence. / Infect Dis Obstet Gynecol 2011, 2011:927861. CrossRef
  25. Yanagawa N, Osakabe M, Hayashi M, Tamura G, Motoyama T: Detection of HPV-DNA, p53 alterations, and methylation in penile squamous cell carcinoma in Japanese men. / Pathol Int 2008, 58:477-82. CrossRef
  26. Giaginis C, Michailidi C, Stolakis V, Alexandrou P, Tsourouflis G, Klijanienko J, Delladetsima I, Theocharis S: Expression of DNA repair proteins MSH2, MLH1 and MGMT in human benign and malignant thyroid lesions: an immunohistochemical study. / Med Sci Monit 2011, 17:BR81-BR90.
  27. Theocharis S, Klijanienko J, Giaginis C, Rodriguez J, Jouffroy T, Girod A, Point D, Tsourouflis G, Sastre-Garau X: Expression of DNA repair proteins, MSH2, MLH1 and MGMT in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients-survival. / J Oral Pathol Med 2011, 40:218-26. CrossRef
  28. Neyaz MK, Kumar RS, Hussain S, Naqvi SH, Kohaar I, Thakur N, Kashyap V, Das BC, Husain SA, Bharadwaj M: Effect of aberrant promoter methylation of FHIT and RASSF1A genes on susceptibility to cervical cancer in a North Indian population. / Biomarkers 2008, 13:597-06. CrossRef
  29. Citron M, Schoenhaus M, Rothenberg H, Kostroff K, Wasserman P, Kahn L, White A, Burns G, Held D, Yarosh D: O6-methylguanine-DNA methyltransferase in normal and malignant tissue of the breast. / Cancer Invest 1994, 12:605-10. CrossRef
  30. Musarrat J, Wilson JA, Abou-Issa H, Wani AA: O(6)-alkylguanine DNA alkyltransferase activity levels in normal, benign and malignant human female breast. / Biochem Biophys Res Commun 1995, 208:688-96. CrossRef
  31. Esteller M, Herman JG: Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer. / Oncogene 2004, 23:1-. CrossRef
  32. Burgers WA, Blanchon L, Pradhan S, de Launoit Y, Kouzarides T, Fuks F: Viral oncoproteins target the DNA methyltransferases. / Oncogene 2007, 26:1650-655. CrossRef
  33. Yuan ZQ, Gault EA, Gobeil P, Nixon C, Campo MS, Nasir L: Establishment and characterization of equine fibroblast cell lines transformed in vivo and in vitro by BPV-1: model systems for equine sarcoids. / Virology 2008, 373:352-61. CrossRef
  34. Strazzullo M, Cossu A, Baldinu P, Colombino M, Satta MP, Tanda F, De Bonis ML, Cerase A, D’Urso M, D’Esposito M, / et al.: High-resolution methylation analysis of the hMLH1 promoter in sporadic endometrial and colorectal carcinomas. / Cancer 2003, 98:1540-546. CrossRef
  35. Schildhaus HU, Krockel I, Lippert H, Malfertheiner P, Roessner A, Schneider-Stock R: Promoter hypermethylation of p16INK4a, E-cadherin, O6-MGMT, DAPK and FHIT in adenocarcinomas of the esophagus, esophagogastric junction and proximal stomach. / Int J Oncol 2005, 26:1493-500.
  36. Scarano MI, Strazzullo M, Matarazzo MR, D’Esposito M: DNA methylation 40 years later: Its role in human health and disease. / J Cell Physiol 2005, 204:21-5. CrossRef
  37. Matarazzo MR, De Bonis ML, Gregory RI, Vacca M, Hansen RS, Mercadante G, D’Urso M, Feil R, D’Esposito M: Allelic inactivation of the pseudoautosomal gene SYBL1 is controlled by epigenetic mechanisms common to the X and Y chromosomes. / Hum Mol Genet 2002, 11:3191-198. CrossRef
  38. Wentzensen N, Sherman ME, Schiffman M, Wang SS: Utility of methylation markers in cervical cancer early detection: appraisal of the state-of-the-science. / Gynecol Oncol 2009, 112:293-99. CrossRef
  39. Jacob R, Shafiei N, Nagel G, Welkoborsky HJ, Mann W, Kaina B: MGMT activity in mucosal epithelium and squamous cell carcinoma of the head and neck. / Anticancer Res 2010, 30:2561-566.
  
• 作者单位：Gennaro Altamura (1)
  Maria Strazzullo (2)
  Annunziata Corteggio (1)
  Romina Francioso (3)
  Franco Roperto (1)
  Maurizio D’Esposito (3) (4)
  Giuseppe Borzacchiello (1)
  
  1. Department of Pathology and Animal health, University of Naples Federico II, Via Veterinaria, 1-80137, Napoli, Italy
  2. Institute for Animal Production System in Mediterranean Environment, National Research Council, Via Argine, 1085 80147, Naples, Italy
  3. Institute of Genetic and Biophysics ABT, National Research Council, Via P.Castellino 111, 80131, Naples, Italy
  4. IRCCS Neuromed, Pozzilli, Italy
  

文摘

Background Bovine papillomaviruses (BPVs) types 1 and 2 are the only known papillomaviruses able to jump the species. In fact, BPVs 1/2 induce neoplasia in their natural bovine host but infection is also associated to neoplastic skin lesions in equids termed sarcoids. The equine sarcoid is considered to be the most common equine cutaneous tumour worldwide for which no effective therapy is available. Very little is known about the molecular mechanisms underlying tumourigenesis, although genes contributing to sarcoid development have been identified. Several studies associate the development of cancer to the loss of function of a number of oncosuppressor genes. In this study the putative role of O6-methylguanine-DNA methyltrasferase (MGMT) was investigated for sarcoids. The expression of the oncosuppressor protein was assessed in normal and sarcoid cells and tissues. In addition, the DNA methylation profile was analysed to assess the role of epigenetic mechanism in regulation of MGMT expression. Results A group of 15 equine sarcoids and two primary sarcoid cell lines (fibroblasts) were analyzed for the expression of MGMT protein by immunohistochemistry, immunofluorescence and Western blotting techniques. The sarcoid cell line EqSO4b and the tumour samples showed a reduction or absence of MGMT expression. To investigate the causes of deregulated MGMT expression, ten samples were analyzed for the DNA methylation profile of the CpG island associated to the MGMT promoter. The analysis of 73 CpGs encompassing the region of interest showed in 1 out of 10 (10%) sarcoids a pronouncedly altered methylation profile when compared to the control epidermal sample. Similarily the EqSO4b cell line showed an altered MGMT methylation pattern in comparison to normal fibroblasts. Conclusion As previously demonstrated for the oncosuppressor gene FHIT, analysis of MGMT expression in sarcoid tissues and a sarcoid-derived fibroblast cell line further suggests that oncosuppressor silencing may be also involved in BPV-induced equine tumours. Abnormal DNA methylation seems to be one of the possible molecular mechanisms involved in the alteration of MGMT expression. Further studies are required to address other basic molecular mechanisms involved in reduced MGMT expression. This study underlines the possible role of DNA methylation in oncosuppressor inactivation in equine sarcoids.