WIF-1 gene methylation in cervical squamous intraepithelial lesions
Objective. To evaluate the diagnostic value of WIF-1 gene promoter region methylation in the development of cervical intraepithelial neoplasia.Sukhikh G.T., Ashrafyan L.A., Bairamova G.R., Babkina I.O., Chernova V.F., Osipyants A.I., Korolkova A.I., Poloznikov A.A., Asfarova G.R., Mullabaeva S.M., Kogan E.A., Muizhnek E.L., Drukh V.M., Kiselev V.I.
Subjects and methods. The investigation included 62 patients aged 18 to 55 years who had come to the Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of the Russian Federation, in the period February to August 2016 for examination and undergone liquid-based cytology, quantitative and qualitative tests for human papillomavirus (HPV), histological examination of cervical biopsy specimens, and extended colposcopy. Bisulfite sequencing was used to study the level of WIF-1 promoter methylation in 62 samples of cells taken from the cervical canal with a cervix brush.
Results. The normal mean level of WIF-1 promoter region methylation was 2.3±5.4%. The women diagnosed with high- or low-grade squamous intraepithelial lesions were observed to have a more statistically significant than normal value (p < 0.0001), abnormal WIF-1 gene promoter region hypermethylation at mean frequencies of 29.2±17.2 and 54.8±18.7%, respectively.
Conclusion. The findings suggest that the level of WIF-1 gene promoter region methylation significantly correlates with the stage of HPV-associated cervical disease. Thus, evaluation of the WIF-1 gene methylation status may be regarded as a potential diagnostic marker for cervical carcinogenesis and a predictive clinical marker during combination treatment for cervical cancer.
Keywords
cervical intraepithelial neoplasia
Wnt-cascade
WIF-1 gene
DNA methylation
epigenetic modification
bisulfite sequencing
References
1. Zaravinos A., Mammas I.N., Sourvinos G., Spandidos D.A. Molecular detection methods of human papillomavirus (HPV). Int. J. Biol. Markers. 2009; 24(4): 215-22.
2. Коган Е.А., Файзуллина Н.М., Ли Ц., Демура Т.А., Жарков Н.В., Козаченко А.В., Байрамова Г.Р., Чернова В.Ф., Прилепская В.Н. Ранняя диагностика ВПЧ-ассоциированной патологии шейки матки у женщин до 30 лет и старше. Акушерство и гинекология. 2015; 9: 62-7. [Kogan E.A., Faizullina N.M., Li Ts., Demura T.A., Zharkov N.V., Kozachenko A.V., Chernova V.F., Bairamova G.R., Prilepskaya V.N. Early diagnosis of HPV-associated disease of the cervix uteri in women aged less than 30 years or older. Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2015; (9): 62-7. (in Russian)
3. Blatt A.J., Kennedy R., Luff R.D., Austin R.M., Rabin D.S. Comparison of cervical cancer screening results among 256,648 women in multiple clinical practices. Cancer Cytopathol. 2015; 123(5): 282-8. doi: 10.1002/cncy.21544.
4. Bairamova G.R., Faizullin L.Z., Korolkova A.I., Poloznikov A.A., Kiselev V.I. Cervical cancer screening: What is new in global practice? Akusherstvo i ginekologiya/Obstetrics and Gynecology. 2016; (7): 17-21. (in Russian) http://dx.doi.org/10.18565/aig.2016.7.17-21
5. Kiselev V.I. Molecular mechanisms of pathogenesis of hyperplastic and dysplastic diseases of the reproductive system and ways of their pharmacological correction. In: Prilepskaya V.N., ed. Cervical pathology and genital infections. Мoscow: MEDpress-inform; 2008: 53-60. (in Russian)
6. Boyer S.N., Wazer D.E., Band V. E7 protein of human papilloma virus-16 induces degradation of retinoblastoma protein through the ubiquitin-proteasome pathway. Cancer Res. 1996; 56(20): 4620-4.
7. Thomas M., Pim D., Banks L. The role of the E6-p53 interaction in the molecular pathogenesis of HPV. Oncogene. 1999; 18(53): 7690-700. doi: 10.1038/sj.onc.1202953.
8. Uren A., Fallen S., Yuan H., Usubütün A., Küçükali T., Schlegel R. et al. Activation of the canonical Wnt pathway during genital keratinocyte transformation: a model for cervical cancer progression. Cancer Res. 2005; 65(14): 6199-206. doi: 10.1158/0008-5472.CAN-05-0455.
9. Curtin J.C., Lorenzi M.V. Drug discovery approaches to target Wnt signaling in cancer stem cells. Oncotarget. 2010; 1(7): 552-66. doi: 10.18632/oncotarget.101016.
10. Hsieh J.C., Kodjabachian L., Rebbert M.L., Rattner A., Smallwood P.M., Samos C.H. et al. A new secreted protein that binds to Wnt proteins and inhibits their activities. Nature. 1999; 398(6726): 431-6. doi: 10.1038/18899.
11. Ai L., Tao Q., Zhong S., Fields C.R., Kim W.-J., Lee M.W. et al. Inactivation of Wnt inhibitory factor-1 (WIF1) expression by epigenetic silencing is a common event in breast cancer. Carcinogenesis. 2006; 27: 1341–8. doi:10.1093/carcin/bgi379.
12. Yee D.S., Tang Y., Li X., Liu Z., Guo Y., Ghaffar S. et al. The Wnt inhibitory factor 1 restoration in prostate cancer cells was associated with reduced tumor growth, decreased capacity of cell migration and invasion and a reversal of epithelial to mesenchymal transition. Mol. Cancer. 2010; 9: 162. doi: 10.1186/1476-4598-9-162.
13. Delmas A.L., Riggs B.M., Pardo C.E., Dyer L.M., Darst R.P., Izumchenko E.G. et al. WIF1 is a frequent target for epigenetic silencing in squamous cell carcinoma of the cervix. Carcinogenesis. 2011; 32: 1625–33. doi:10.1093/carcin/bgr193.
14. Ramachandran I., Thavathiru E., Ramalingam S., Natarajan G., Mills W.K., Benbrook D.M. et al. Wnt inhibitory factor 1 induces apoptosis and inhibits cervical cancer growth, invasion and angiogenesis in vivo. Oncogene. 2012; 31(22): 2725-37. doi: 10.1038/onc.2011.455.
15. Urakami S., Shiina H., Enokida H., Hirata H., Kawamoto K., Kawakami T. et al. Wnt antagonist family genes as biomarkers for diagnosis, staging, and prognosis of renal cell carcinoma using tumor and serum DNA. Clin. Cancer Res. 2006; 12(23): 6989-97. doi: 10.1158/1078-0432.CCR-06-1194.
16. Issa J.P. Cancer prevention: epigenetics steps up to the plate. Cancer Prev. Res. (Phila) 2008; 1(4): 219-22. doi: 10.1158/1940-6207.CAPR-08-0029.
17. Esteller M. Epigenetics in cancer. N. Engl. J. Med. 2008; 358(11): 1148-59. doi: 10.1056/NEJMra072067.
18. Laird P.W. Cancer epigenetics. Hum. Mol. Genet. 2005; 14(Spec No): R65-76. doi: 10.1093/hmg/ddi113.
19. Deng Y., Yu B., Cheng Q., Jin J., You H., Ke R. et al. Epigenetic silencing of WIF-1 in hepatocellular carcinomas. J. Cancer Res. Clin. Oncol. 2010; 136(8): 1161-7. doi: 10.1007/s00432-010-0763-5.
20. Gao Z., Xu Z., Hung M-S., Lin Y-C., Wang T., Gong M. et al. Promoter demethylation of WIF-1 by epigallocatechin-3-gallate in lung cancer cells. Anticancer Res. 2009; 29(6): 2025-30.
21. Kumaki Y., Oda M., Okano M. QUMA: quantification tool for methylation analysis. Nucleic. Acids Res. 2008; 36: W170-5. doi:10.1093/nar/gkn294.
22. Van Der Meide W.F., Snellenberg S., Meijer C.J.L.M., Baalbergen A., Helmerhorst T.J.M., Van Der Sluis W.B. et al. Promoter methylation analysis of WNT/β-catenin signaling pathway regulators to detect adenocarcinoma or its precursor lesion of the cervix. Gynecol. Oncol. 2011; 123(1): 116-22. doi: 10.1016/j.ygyno.2011.06.015.
23. Kan Y.-Y., Liou Y.-L., Wang H.-J., Chen C.-Y., Sung L.-C., Chang C.-F. et al. PAX1 Methylation as a Potential Biomarker for Cervical Cancer Screening. Int. J. Gynecol. Cancer. 2014; 24: 928–34. doi:10.1097/IGC.0000000000000155.
24. Kato K., Long N.K., Makita H., Toida M., Yamashita T., Hatakeyama D. et al. Effects of green tea polyphenol on methylation status of RECK gene and cancer cell invasion in oral squamous cell carcinoma cells. Br. J. Cancer. 2008; 99: 647–54. doi:10.1038/sj.bjc.6604521.
Received 06.12.2016
Accepted 23.12.2016
About the Authors
Sukhikh Gennady Tikhonovich, Doctor of Medical Sciences, Professor, Academician of the Russian Academy of Sciences, Director of the Research Center of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia. 117997, Russia, Moscow, Ac. Oparina str. 4. Tel.: +74954381866. E-mail: g_sukhikh@oparina4.ruAshrafyan Lev Andreevich, Doctor of Medical Sciences, Honored Doctor of the Russian Federation, Professor, Head of the Laboratory of Combined Methods for the Treatment of Gynecological Diseases of the Russian Research Center of Roentgenology and Radiology, Ministry of Health of Russia.
117485, Russia, Moscow, Profsoyuznaya str. 86. Tel.: +79857402745
Bayramova Gyuldana Raufovna, doctor of medical sciences, head of the clinical work of the scientific and polyclinic department of the Clinical Department, Research Center of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia.
117997, Russia, Moscow, Ac. Oparina str. 4. Tel.: +74954381866. E-mail: g_bairamova@oparina4.ru
Babkina Irina Olegovna: laboratory assistant-researcher of the laboratory of infectious immunology, D. Rogachev Federal Research Clinical Center of Pediatric Hematology, Oncology, and Immunology, Ministry of Health of Russia.
117997, Russia, Moscow, GSP-7, Samora Mashela str. 1. Tel.: +74952876570, ext. 5509. E-mail: iobabkina@gmail.com
Chernova Viktoria Fedorovna, post-graduate student of the polyclinic department, Research Center of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia. 117997, Russia, Moscow, Ac. Oparina str. 4. Tel.: +74954381866. E-mail: v_chernova@oparina4.ru
Osipyants Andrey Igorevich, researcher, Laboratory of Biochemistry and Enzymology, D. Rogachev Federal Research Clinical Center of Pediatric Hematology,
Oncology, and Immunology, Ministry of Health of Russia. 117997, Russia, Moscow, GSP-7, Samora Mashela str. 1. Tel.: +79032947414. E-mail: osssip@gmail.com
Korolkova Anna Igorevna, post-graduate student of the I year of training, Research Center of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia.
117997, Russia, Moscow, Ac. Oparina str. 4. Tel.: +79153220879. E-mail: zaikinaai@icloud.com
Poloznikov Andrey Aleksandrovich, Candidate of Chemical Sciences, Head of the Laboratory of Biochemistry and Enzymology, D. Rogachev
Federal Research Clinical Center of Pediatric Hematology, Oncology, and Immunology, Ministry of Health of Russia.
117997, Russia, Moscow, GSP-7, Samora Mashela str. 1. Tel.: +74952876570, ext. 5509. E-mail: andrey.poloznikov@gmail.com
Asfarova Gunay Raisovna, Post-graduate student of the I year of training, Research Center of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia.
117997, Russia, Moscow, Ac. Oparina str. 4. Tel.: +79262621113. E-mail: gunyt@mail.ru
Mullabaeva Svetlana Mininhaevna, the head of the laboratory for the collection and storage of biomaterials, Research Center of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia. 117997, Russia, Moscow, Ac. Oparina str. 4. Tel.: +79153220879. E-mail: s_mullabaeva@oparina4.ru
Kogan Evgenia Aleksandrovna, Doctor of Medical Sciences, Professor, Academician A.I. Strukov Department of Pathological Anatomy, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia. 119991, Russia, Moscow, Trubetskaya str. 8-2. Tel.: +74992480181. E-mail: expedition@mma.ru
Mouizhnek Ekaterina Leonidovna, Candidate of Biological Sciences, Director for Science, ZAO “MiraxBioFarma”.
121248, Russia, Moscow, Kutuzov Ave, 12, p. 2. Tel.: +74957212058. E-mail: MuyzhnekEL@ilmixgroup.ru
Druh Vadim Mikhailovich, Candidate of Medical Sciences, Head of Scientific Projects, Institute of Biomedical Problems, Peoples’ Friendship University of Russia.
117198, Russia, Moscow, Miklukho-Maklaya str. 6. Tel.: +74957212058. E-mail: druhvm@gmail.com
Kiselev Vsevolod Ivanovich, Doctor of Biological Sciences, Professor, Corresponding Member. RAS, Chief Scientific Officer of the Research Department of Early Carcinogenesis, Prevention, Diagnosis and Comprehensive Treatment of Oncological Diseases of Female Reproductive Organs, Russian Research Center of Roentgenology and Radiology, Ministry of Health of Russia. 117485, Russia, Moscow, Profsoyuznaya str. 86. Tel.: +79857763116. E-mail: vkis10@mail.ru
For citations: Sukhikh G.T., Ashrafyan L.A., Bairamova G.R., Babkina I.O., Chernova V.F., Osipyants A.I., Korolkova A.I., Poloznikov A.A., Asfarova G.R., Mullabaeva S.M., Kogan E.A., Muizhnek E.L., Drukh V.M., Kiselev V.I. Investigation of WIF-1 gene methylation in cervical squamous intraepithelial lesions. Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2017; (5): 114-23. (in Russian)
http://dx.doi.org/10.18565/aig.2017.5.114-23
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