{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T22:41:29Z","timestamp":1791240089014,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2015,2,3]],"date-time":"2015-02-03T00:00:00Z","timestamp":1422921600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Medical Virology"],"published-print":{"date-parts":[[2015,6]]},"abstract":"<jats:sec><jats:label\/><jats:p>E2 protein binding to the four E2 binding sites (E2BSs) at the long control region of Human Papillomavirus (HPV) 16\/18 genome may exert either transcriptional activation\/repression on E6 and E7 oncoproteins. Methylation status at the E2BSs may affect the relative binding of E2 protein to them. In this study, methylation percentage at E2BS 1, 2 (promoter\u2010proximal), and 4 (promoter\u2010distal) were assessed by pyrosequencing and compared among HPV 16\/18\u2010positive cervical cancer, high\u2010grade, and low\u2010grade Cervical Intraepithelial Neoplasia, Atypical Squamous Cells of Undetermined Significance, and normal cervical epithelium. HPV 16 E2BS1&amp;2 were more methylated than HPV 16 E2BS4 in cervical cancer whereas in cervical premalignant lesions and normal epithelium, HPV 16 E2BS1&amp;2 were less methylated than HPV 16 E2BS4. HPV 18 E2BS1&amp;2 remained more methylated than E2BS4 in all histological groups. HPV 16 E2BS1&amp;2 methylation increased from high\u2010grade lesions to cervical cancer (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001). HPV 16 E2BS4 methylation increased from low\u2010grade to high\u2010grade premalignant lesions (<jats:italic>P<\/jats:italic>\u2009=\u20090.041). Both HPV 18 E2BS1&amp;2 and E2BS4 methylation increased from low\u2010grade to high\u2010grade Cervical Intraepithelial Neoplasia (<jats:italic>P<\/jats:italic>\u2009=\u20090.019 and 0.001 respectively) and further increased form high\u2010grade lesions to cervical cancer (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001 and 0.005 respectively). Conclusively, HPV 16 E2BS1&amp;2 (for transcriptional repression of E6\/E7 oncoproteins) became more heavily methylated than E2BS4 (for transcriptional activation of E6\/E7) in cervical cancer, favouring the differential binding of E2 protein to E2BS4. Increasing methylation at HPV 16\/18 E2BSs are potentially useful adjunctive molecular markers for predicting progression from low\u2010grade to high\u2010grade cervical premalignant lesions and from high\u2010grade lesions to cervical cancer. <jats:bold><jats:italic>J. Med. Virol. 87:1022\u20131033, 2015<\/jats:italic>.<\/jats:bold> \u00a9 2015 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jmv.24129","type":"journal-article","created":{"date-parts":[[2015,2,3]],"date-time":"2015-02-03T17:06:09Z","timestamp":1422983169000},"page":"1022-1033","source":"Crossref","is-referenced-by-count":31,"title":["HPV 16 E2 binding sites 1 and 2 become more methylated than E2 binding site 4 during cervical carcinogenesis"],"prefix":"10.1002","volume":"87","author":[{"given":"Tsin\u2010Wah","family":"Leung","sequence":"first","affiliation":[{"name":"Department of Obstetrics &amp; Gynaecology Li Ka Shing Faculty of Medicine University of Hong Kong Hong Kong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie S.","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics &amp; Gynaecology Li Ka Shing Faculty of Medicine University of Hong Kong Hong Kong 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