Original Article

Comparison of methylation patterns of E6 gene promoter region in the low-risk and high-risk human papillomavirus


Background and Objectives: Cervical cancer is an important cause of death in women worldwide (1, 2). Cancer is a disease that may be caused by many factors that affect gene activity through genetic and epigenetic changes like DNA methylation. DNA promoter methylation contributes to the chromatin conformation that may be repressing transcription of the human papilloma virus type16 (HPV-16), which is prevalent in the etiology of cervical carcinoma. In the present study, we aimed to investigate DNA methylation target sites in promoter region of both high-risk and low risk HPVs.
Materials and Methods: Methylation pattern of E6 promoter in low-risk HPV (type 11) and high-risk HPV (type 16 and 18) was examined by Bisulfite Sequencing PCR (BSP) method.
Results: Based on the results, methylation status of high-risk and low-risk HPV-E6 promoter is different. It was revealed that CpG dinucleotides were unmethylated in type 16 and 18 target sequences, whereas in HPV-E6 type 11 all of CpG dinucleotides were methylated except one of them.
Conclusion: The result suggested that a significant correlation between methylation status and HPV-induced cervical carcinogenesis, and promoter of HPV-16 and 18 E6 has minimal methylation in comparison with low-risk HPV-11.

Forman D, de Martel C, Lacey CJ, Soerjomataram I, Lortet-Tieulent J, Bruni L, et al. Global burden of human papillomavirus and related diseases. Vaccine. 2012;30:F12-F23.

Saadat P, Soleimanjahi H, Asghari SM, Fazeli M, Razavinikoo H, Karimi H. Co-Administration of Anti-Angiogenic Peptide and DNA Vaccine in Cervical Cancer Tumor Model. Int J Cancer Manag. 2017;10(3).

Mukhtar R, Mehmood R, Parveen S, Hussain M, Arif M. prevalence of cervical cancer in developing country: Pakistan. Glob J Med Res. 2015.

Organization WH. Cervical cancer screening in developing countries: report of a WHO consultation: World Health Organization; 2002.

Moreman C, Redman C, Moss E. Human Papillomavirus and Its Role in Cervical Cancer Screening and Treatment. Curr Treat Options Infect Dis. 2015;7(3):217-29.

McBride AA, Warburton A. The role of integration in oncogenic progression of HPV-associated cancers. PLoS Pathog. 2017;13(4):e1006211.

Furumoto H, Irahara M. Human papilloma virus (HPV) and cervical cancer. J Med Invest. 2002;49(3/4):124-33.

Burd EM. Human papillomavirus and cervical cancer. Clin Microbiol Rev. 2003;16(1):1-17.

Crosbie EJ, Einstein MH, Franceschi S, Kitchener HC. Human papillomavirus and cervical cancer. Lancet. 2013;382(9895):889-99.

Juckett G, Hartman-Adams H. Human papillomavirus: clinical manifestations and prevention. Am Fam Physician. 2010;82(10):1209.

Herbert J, Coffin J. Reducing patient risk for human papillomavirus infection and cervical cancer. J Am Osteopath Assoc. 2008;108(2):65.

Mishra GA, Pimple SA, Shastri SS. An overview of prevention and early detection of cervical cancers. Indian J Med Paediatr Oncol. 2011;32(3):125.

Dijkstra M, Snijders P, Arbyn M, Rijkaart D, Berkhof J, Meijer C. Cervical cancer screening: on the way to a shift from cytology to full molecular screening. Ann Oncol. 2014;25(5):927-35.

Moody CA, Laimins LA. Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer. 2010;10(8):550.

Jiménez-Wences H, Peralta-Zaragoza O, Fernández-Tilapa G. Human papilloma virus, DNA methylation and microRNA expression in cervical cancer. Oncol Rep. 2014;31(6):2467-76.

Badal V, Chuang LS, Tan EH-H, Badal S, Villa LL, Wheeler CM, et al. CpG methylation of human papillomavirus type 16 DNA in cervical cancer cell lines and in clinical specimens: genomic hypomethylation correlates with carcinogenic progression. J Virol. 2003;77(11):6227-34.

Zheng Z-M, Baker CC. Papillomavirus genome structure, expression, and post-transcriptional regulation. Front Biosci. 2006;11:2286.

Bellanger S, Tan CL, Xue YZ, Teissier S, Thierry F. Tumor suppressor or oncogene? A critical role of the human papillomavirus (HPV) E2 protein in cervical cancer progression. Am J Cancer Res. 2011;1(3):373.

Klingelhutz AJ, Roman A. Cellular transformation by human papillomaviruses: lessons learned by comparing high-and low-risk viruses. Virology. 2012;424(2):77-98.

Carson A, Khan SA. Characterization of transcription factor binding to human papillomavirus type 16 DNA during cellular differentiation. J Virol. 2006;80(9):4356-62.

Williams VM, Filippova M, Soto U, Duerksen-Hughes PJ. HPV-DNA integration and carcinogenesis: putative roles for inflammation and oxidative stress. Future Virol. 2011;6(1):45-57.

Bonello K, Blundell R. The Role of the Human Papillomavirus (HPV) in Cervical Cancer: A Review about HPV-Induced Carcinogenesis and Its Epidemiology, Diagnosis, Management and Prevention. Int J Med Students. 2016;4(1):26-32.

Soto D, Song C, McLaughlin-Drubin ME. Epigenetic Alterations in Human Papillomavirus-Associated Cancers. Viruses. 2017;9(9):248.

Yeung A, Lam C, Tsang WP, Tsang TY, Co NN, Yau PL, et al. HPV-16 E6 upregulation of DNMT1 through repression of tumor suppressor p53. Oncol Rep. 2010;24(6):1599-604.

Clarke MA, Wentzensen N, Mirabello L, Ghosh A, Wacholder S, Harari A, et al. Human papillomavirus DNA methylation as a potential biomarker for cervical cancer. Cancer Epidemiol Biomarkers Prev. 2012:cebp. 0905.2012.

Sahasrabuddhe VV, Luhn P, Wentzensen N. Human papillomavirus and cervical cancer: biomarkers for improved prevention efforts. Future Microbiol. 2011;6(9):1083-98.

Vinokurova S, von Knebel Doeberitz M. Differential methylation of the HPV 16 upstream regulatory region during epithelial differentiation and neoplastic transformation. PLoS One. 2011;6(9):e24451.

Hasanzadeh M, Ahmadi S. New Topics on HPV in Eurogin 2016. Obstet Gynecol. 2016;1(2):e8290.

Johannsen E, Lambert PF. Epigenetics of human papillomaviruses. Virology. 2013;445(1-2):205-12.

Sen P, Ganguly P, Ganguly N. Modulation of DNA methylation by human papillomavirus E6 and E7 oncoproteins in cervical cancer. Oncol Lett. 2018;15(1):11-22.

Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands.

Proc Natl Acad Sci U S A. 1996;93(18):9821-6.

Wentzensen N, Sun C, Ghosh A, Kinney W, Mirabello L, Wacholder S, et al. Methylation of HPV18, HPV31, and HPV45 genomes and cervical intraepithelial neoplasia grade 3. J Natl Cancer Inst. 2012;104(22):1738-49.

IssueVol 10 No 6 (2018) QRcode
SectionOriginal Article(s)
Cervical cancer Methylation Human papilloma virus Promoter

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How to Cite
Zafari E, Soleimanjahi H, Samiee S, Razavinikoo H, Farahmand Z. Comparison of methylation patterns of E6 gene promoter region in the low-risk and high-risk human papillomavirus. Iran J Microbiol. 2019;10(6):441-446.