About
The Journal "Obstetrics and Gynecology"Journal HistoryAims and ScopePolicies on Conflict of Interest, Human and Animal Rights, and Informed ConsentEditorial ProcessData sharing statementAdvertising PolicyThe Process for Handling Cases Requiring Corrections, Retractions, and Editorial Expressions of ConcernEditorial BoardEditorial CounsilInformation for ProfessionalsNewsContacts
ArchiveEthical StandardsSubscription
For authors
InstructionsInformed consent policyContract offerEASE GuidelinesICJME CriteriaWAME Recommendations on ChatGPT and Chatbots in Relation to Scholarly Publications
Reviewing
Procedure for reviewingReviewers 2023-2024
About
The Journal "Obstetrics and Gynecology"Journal HistoryAims and ScopePolicies on Conflict of Interest, Human and Animal Rights, and Informed ConsentEditorial ProcessData sharing statementAdvertising PolicyThe Process for Handling Cases Requiring Corrections, Retractions, and Editorial Expressions of ConcernEditorial BoardEditorial CounsilInformation for ProfessionalsNewsContacts
ArchiveEthical StandardsSubscription
For authors
InstructionsInformed consent policyContract offerEASE GuidelinesICJME CriteriaWAME Recommendations on ChatGPT and Chatbots in Relation to Scholarly Publications
Reviewing
Procedure for reviewingReviewers 2023-2024
Logout
Obstetrics and Gynegology2024№5
Epigenetic alterations in patients with...

Epigenetic alterations in patients with cervical intraepithelial neoplasia

DOI
https://dx.doi.org/10.18565/aig.2023.309

Levakov S.A., Dzhafarova M.M., Kaviladze M.G., Guseinova Sh.T., Mushkyurova D.R.

I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of Russia, Moscow, Russia

Despite numerous basic studies on the issues of malignant degeneration of precancerous diseases of the cervix and the widespread introduction of screening programs, mortality from cervical cancer continues to take the leading positions. Currently, there are no reliable prognostic criteria for malignancy of squamous cervical intraepithelial neoplasia (CIN).
The results of recent studies indicated that epigenetic regulation of gene expression plays a fundamental role in the pathogenesis of numerous malignant neoplasms including cervical cancer. The analysis of the literature data showed that squamous cell metaplasia in the cervical transformation zone is affected by cholinergic signaling. Acetylcholine and its receptors do not only regulate the processes of inflammation and proliferation of the normal cells, but they also play an important role in response to oncological processes by increasing the expression of certain receptor subunits, they inhibit apoptosis and increase the likelihood of metastasis. Thus, epigenetic modifications associated with dysplastic and metaplastic processes can serve as a powerful tool for risk stratification, prediction and treatment of cervical neoplasms caused by human papillomavirus (HPV).
Conclusion: The development of a panel of molecular predictors for accurate differential diagnosis of the degree of lesion, as well as identification of the risk group for the transition of dysplasia to cancer, will improve the examination algorithms and make it possible to timely initiate pathogenetic therapy in patients with HPV-associated cervical diseases.

Authors' contributions: Levakov S.A. – developing the concept and design of the study; Dzhafarova M.M., Kaviladze M.G., Guseinova Sh.T. – collecting and performing the analysis of literary data, writing the text; Mushkyurova D.R. – editing the text of the article.
Conflicts of interest: The authors declare no possible conflicts of interest.
Funding: The study was conducted without sponsorship.
For citation: Levakov S.A., Dzhafarova M.M., Kaviladze M.G., Guseinova Sh.T., Mushkyurova D.R. 
Epigenetic alterations in patients with cervical intraepithelial neoplasia.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2024; (5): 5-12 (in Russian)
https://dx.doi.org/10.18565/aig.2023.309

Keywords

cervical intraepithelial neoplasia
LSIL
HSIL
NILM
cervical cancer
human papillomavirus
high carcinogenic risk
fertility
epigenetics
nicotine acetylcholine receptors
Full text (in Russian)

References

  1. Calleja-Macias I.E., Kalantari M., Bernard H.U. Cholinergic signaling through nicotinic acetylcholine receptors stimulates the proliferation of cervical cancer cells: an explanation for the molecular role of tobacco smoking in cervical carcinogenesis? Int. J. Cancer. 2009; 124(5): 1090-6. https://dx.doi.org/ 10.1002/ijc.24053.
  2. Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021; 71(3):209-49. https://dx.doi.org/10.3322/caac.21660.
  3. Dudea-Simon M., Mihu D., Pop L.A., Ciortea R., Malutan A.M., Diculescu D. et al. Alteration of gene and miRNA expression in cervical intraepithelial neoplasia and cervical cancer. Int. J. Mol. Sci. 2022; 23(11): 6054. https://dx.doi.org/10.3390/ ijms23116054.
  4. Liu Y., Qian J., Sun Z., Zhangsun D., Luo S. Cervical cancer correlates with the differential expression of nicotinic acetylcholine receptors and reveals therapeutic targets. Mar. Drugs. 2019; 17(5): 256. https://dx.doi.org/ 10.3390/md17050256.
  5. Gius D., Funk M.C., Chuang E.Y., Feng S., Huettner P.C., Nguyen L. et al. Profiling microdissected epithelium and stroma to model genomic signatures for cervical carcinogenesis accommodating for covariates. Cancer Res. 2007; 67: 7113-23. https://dx.doi.org/ 10.1158/0008-5472.CAN-07-0260.
  6. Graham S.V. Keratinocyte differentiation-dependent human papillomavirus gene regulation. Viruses. 2017; 9(9): 245. https://dx.doi.org/10.3390/v9090245.
  7. Zhang L., Wu J., Ling M.T., Zhao L., Zhao K.N. The role of the PI3K/Akt/mTOR signalling pathway in human cancers induced by infection with human papillomaviruses. Mol. Cancer. 2015; 14: 87. https://dx.doi.org/10.1186/s12943-015-0361-x.
  8. Scheffner M., Werness B.A., Huibregtse J.M., Levine A.J., Howley P.M. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell. 1990; 63(6): 1129-36. https://dx.doi.org/10.1016/0092-8674(90)90409-8.
  9. Münger K., Basile J.R., Duensing S., Eichten A., Gonzalez S.L., Grace M. et al. Biological activities and molecular targets of the human papillomavirus E7 oncoprotein. Oncogene. 2001; 20(54): 7888-98. https://dx.doi.org/10.1038/sj.onc.1204860.
  10. Botezatu A., Iancu I.V., Plesa A., Manda D., Popa O., Bostan M. et al. Methylation of tumour suppressor genes associated with thyroid cancer. Cancer Biomark. 2019; 25(1): 53-65. https://dx.doi.org/10.3233/CBM-182265.
  11. Chabeda A., Yanez R.J.R., Lamprecht R., Meyers A.E., Rybicki E.P, Hitzeroth I.I. Therapeutic vaccines for high-risk HPV-associated diseases. Papillomavirus Res. 2018; 5: 46-58. https://dx.doi.org/10.1016/j.pvr.2017.12.006.
  12. Wentzensen N., Sherman M.E., Schiffman M., Wang S.S. Utility of methylation markers in cervical cancer early detection: appraisal of the state-of-the-science. Gynecol. Oncol. 2009; 112(2): 293-9. https://dx.doi.org/10.1016/j.ygyno.2008.10.012.
  13. Fang J., Zhang H., Jin S. Epigenetics and cervical cancer: from pathogenesis to therapy. Tumour Biol. 2014; 35(6): 5083-93. https://dx.doi.org/10.1007/s13277-014-1737-z.
  14. Zhao X., Cui Y., Li Y., Liang S., Zhang Y., Xie L. et al. [Significance of TSLC1 gene methylation and TSLC1 protein expression in the progression of cervical lesions]. Zhonghua Zhong Liu Za Zhi. 2015; 37(5): 356-60. Chinese.
  15. Laengsri V., Kerdpin U., Plabplueng C., Treeratanapiboon L., Nuchnoi P. Cervical cancer markers: epigenetics and microRNAs. Lab. Med. 2018; 49(2): 97-111. https://dx.doi.org/10.1093/labmed/lmx080.
  16. Tornesello M.L., Faraonio R., Buonaguro L., Annunziata C., Starita N., Cerasuolo A. et al. The role of microRNAs, long non-coding RNAs, and circular RNAs in cervical cancer. Front. Oncol. 2020; 10:150. https://dx.doi.org/10.3389/fonc.2020.00150.
  17. Lui W.O., Pourmand N., Patterson B.K., Fire A. Patterns of known and novel small RNAs in human cervical cancer. Cancer Res. 2007; 67(13): 6031-43. https://dx.doi.org/10.1158/0008-5472.CAN-06-0561.
  18. Pardini B., De Maria D., Francavilla A., Di Gaetano C., Ronco G., Naccarati A. MicroRNAs as markers of progression in cervical cancer: a systematic review. BMC Cancer. 2018; 18(1): 696. doi: 10.1186/s12885-018-4590-4.
  19. He Y., Lin J., Ding Y., Liu G., Luo Y., Huang M. et al. A systematic study on dysregulated microRNAs in cervical cancer development. Int. J. Cancer. 2016; 138(6): 1312-27. doi: 10.1002/ijc.29618.
  20. Wang X., Wang H.K., McCoy J.P., Banerjee N.S., Rader J.S., Broker T.R. et al. Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6. RNA. 2009; 15(4): 637-47. https://dx.doi.org/10.1261/rna.1442309.
  21. Aalijahan H., Ghorbian S. Long non-coding RNAs and cervical cancer. Exp. Mol. Pathol. 2019; 106: 7-16. https://dx.doi.org/10.1016/j.yexmp.2018.11.010.
  22. Kim H.J., Lee D.W., Yim G.W., Nam E.J., Kim S., Kim S.W. et al. Long non-coding RNA HOTAIR is associated with human cervical cancer progression. Int. J. Oncol. 2015; 46(2): 521-30. doi: 10.3892/ijo.2014.2758.
  23. Jiang Y., Li Y., Fang S., Jiang B., Qin C., Xie P. et al. The role of MALAT1 correlates with HPV in cervical cancer. Oncol. Lett. 2014; 7(6): 2135-41. https://dx.doi.org/10.3892/ol.2014.1996.
  24. Wessler I., Kirkpatrick C.J. Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br. J. Pharmacol. 2008; 154(8): 1558-71. https://dx.doi.org/10.1038/bjp.2008.185.
  25. Bierut L.J. Nicotine dependence and genetic variation in the nicotinic receptors. Drug Alcohol Depend. 2009; 104 Suppl 1(Suppl 1): S64-9. https://dx.doi.org/10.1016/j.drugalcdep.2009.06.003.
  26. Cheng K., Samimi R., Xie G., Shant J., Drachenberg C., Wade M. et al. Acetylcholine release by human colon cancer cells mediates autocrine stimulation of cell proliferation. Am. J. Physiol. Gastrointest. Liver Physiol. 2008; 295(3): G591-7. https://dx.doi.org/10.1152/ajpgi.00055.2008.
  27. Pettersson A., Nylund G., Khorram-Manesh A., Nordgren S., Delbro D.S. Nicotine induced modulation of SLURP-1 expression in human colon cancer cells. Auton. Neurosci. 2009; 148(1-2): 97-100. https://dx.doi.org/10.1016/j.autneu.2009.03.002.
  28. Song P., Sekhon H.S., Jia Y., Keller J.A., Blusztajn J.K., Mark G.P. et al. Acetylcholine is synthesized by and acts as an autocrine growth factor for small cell lung carcinoma. Cancer Res. 2003; 63(1): 214-21.
  29. Cuny H., Yu R., Tae H.S., Kompella S.N., Adams D.J. α-Conotoxins active at α3-containing nicotinic acetylcholine receptors and their molecular determinants for selective inhibition. Br. J. Pharmacol. 2018; 175(11): 1855-68. https://dx.doi.org/10.1111/bph.13852.
  30. Chen C.S., Lee C.H., Hsieh C.D., Ho C.T., Pan M.H., Huang C.S. et al. Nicotine-induced human breast cancer cell proliferation attenuated by garcinol through down-regulation of the nicotinic receptor and cyclin D3 proteins. Breast Cancer Res. Treat. 2011; 125(1): 73-87. https://dx.doi.org/10.1007/s10549-010-0821-3.
  31. Sun H., Ma X. α5-nAChR modulates nicotine-induced cell migration and invasion in A549 lung cancer cells. Exp. Toxicol. Pathol. 2015; 67(9): 477-82. https://dx.doi.org/10.1016/j.etp.2015.07.001.
  32. Tu S.H., Ku C.Y., Ho C.T., Chen C.S., Huang C.S., Lee C.H. et al. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits nicotine- and estrogen-induced α9-nicotinic acetylcholine receptor upregulation in human breast cancer cells. Mol. Nutr. Food Res. 2011; 55(3): 455-66. https://dx.doi.org/10.1002/mnfr.201000254.
  33. Trombino S., Cesario A., Margaritora S., Granone P., Motta G., Falugi C. et al. Alpha7-nicotinic acetylcholine receptors affect growth regulation of human mesothelioma cells: role of mitogen-activated protein kinase pathway. Cancer Res. 2004; 64(1): 135-45. https://dx.doi.org/10.1158/0008-5472.can-03-1672.
  34. Jia Y., Sun H., Wu H., Zhang H., Zhang X., Xiao D. et al. Nicotine inhibits cisplatin-induced apoptosis via regulating α5-nAChR/AKT signaling in human gastric cancer cells. PLoS One. 2016; 11(2): e0149120. https://dx.doi.org/10.1371/journal.pone.0149120.
  35. Liu K., Liu Y., Yu Y., Feng T., Zhang S. Identification of acetylcholine-related enzymes and the role of acetylcholine and nicotine in human cervical cancer. Int. J. Clin. Exp. Pathol. 2016; 9(4): 4854-61.
  36. Calleja-Macias I.E., Kalantari M., Bernard H.U. Cholinergic signaling through nicotinic acetylcholine receptors stimulates the proliferation of cervical cancer cells: an explanation for the molecular role of tobacco smoking in cervical carcinogenesis? Int. J. Cancer. 2009; 124(5): 1090-6. https://dx.doi.org/10.1002/ijc.24053.
  37. Smedlund K., Tano J.Y., Margiotta J., Vazquez G. Evidence for operation of nicotinic and muscarinic acetylcholine receptor-dependent survival pathways in human coronary artery endothelial cells. J. Cell. Biochem. 2011; 112(8): 1978-84. https://dx.doi.org/10.1002/jcb.23169.
  38. Li D.J., Fu H., Tong J., Li Y.H, Qu L.F., Wang P. et al Cholinergic anti-inflammatory pathway inhibits neointimal hyperplasia by suppressing inflammation and oxidative stress. Redox. Biol. 2018; 15: 22-33. https://dx.doi.org/10.1016/j.redox.2017.11.013.
  39. Arredondo J., Chernyavsky A.I., Jolkovsky D.L., Pinkerton K.E., Grando S.A. Receptor-mediated tobacco toxicity: cooperation of the Ras/Raf-1/MEK1/ERK and JAK-2/STAT-3 pathways downstream of alpha7 nicotinic receptor in oral keratinocytes. FASEB J. 2006; 20(12): 2093-101. https://dx.doi.org/10.1096/fj.06-6191com.
  40. Nakayama H., Numakawa T., Ikeuchi T. Nicotine-induced phosphorylation of Akt through epidermal growth factor receptor and Src in PC12h cells. J. Neurochem. 2002; 83(6): 1372-9. https://dx.doi.org/10.1046/j.1471-4159.2002.01248.x.
  41. Vieira-Alves I., Coimbra-Campos L.M.C., Sancho M., da Silva R.F., Cortes S.F., Lemos V.S. Role of the α7 nicotinic acetylcholine receptor in the pathophysiology of atherosclerosis. Front Physiol. 2020; 11: 621769. https://dx.doi.org/10.3389/fphys.2020.621769.
  42. Шулепко М.А., Бычков М.Л., Кульбацкий Д.С., Люкманова Е.Н. Никотиновые ацетилхолиновые рецепторы человека. Часть II: Не-нейрональная холинергическая система. Биоорганическая химия. 2019; 45(3): 227-37. [Shulepko M.A., Kulbatskii D.S., Bychkov M.L., Lyukmanova E.N. Human nicotinic acetylcholine receptors: Part II. Non-neuronal cholinergic system. Russian Journal of Bioorgfnic Chemistry. 2019; 45(3): 227-37. https://dx.doi.org/10.1134/S0132342319020131.
  43. Prokopczyk B., Cox J.E., Hoffmann D., Waggoner S.E. Identification of tobacco-specific carcinogen in the cervical mucus of smokers and nonsmokers. J. Natl. Cancer Inst. 1997; 89(12): 868-73. https://dx.doi.org/10.1093/jnci/89.12.868.
  44. Fonseca-Moutinho J.A. Smoking and cervical cancer. ISRN Obstet. Gynecol. 2011; 2011: 847684. https://dx.doi.org/10.5402/2011/847684.
  45. Jensen K.E., Schmiedel S., Frederiksen K., Norrild B., Iftner T., Kjær S.K. Risk for cervical intraepithelial neoplasia grade 3 or worse in relation to smoking among women with persistent human papillomavirus infection. Cancer Epidemiol. Biomarkers Prev. 2012; 21(11):1949-55. https://dx.doi.org/10.1158/1055-9965.EPI-12-0663.

Received 29.12.2023

Accepted 22.05.2024

About the Authors

Sergey A. Levakov, Dr. Med. Sci., Professor, Head of the Department of Obstetrics and Gynecology, N.V. Sklifosovsky ICM, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University), 119991, Russia, Moscow, Trubetskaya str., 8, bld. 2, +7(495)609-14-00, levakoff@yandex.ru,
https://orcid.org/0000-0002-4591-838X
Makhluga M. Dzhafarova, PhD student of the Department of Obstetrics and Gynecology, N.V. Sklifosovsky ICM, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University), 119991, Russia, Moscow, Trubetskaya str., 8, bld. 2, +7(495)609-14-00, qoqlu55@mail.ru
Mariami G. Kaviladze, PhD student, Teaching Assistant at the Department of Obstetrics and Gynecology, N.V. Sklifosovsky ICM, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University), 119991, Russia, Moscow, Trubetskaya str., 8, bld. 2, +7(495)609-14-00, mariam-kaviladze@mail.ru,
https://orcid.org/0000-0003-0221-5673
Shirin T. Guseynova, Student, N.V. Sklifosovsky ICM, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University),
119991, Russia, Moscow, Trubetskaya str., 8, bld. 2, +7(495)609-14-00, guseinova.shirin@mail.ru, https://orcid.org/0009-0008-6967-7497
Diana R. Mushkyurova, PhD student of the Department of Obstetrics and Gynecology, N.V. Sklifosovsky ICM, I.M. Sechenov First Moscow State Medical University,
Ministry of Health of Russia (Sechenov University), 119991, Russia, Moscow, Trubetskaya str., 8, bld. 2, +7(495)609-14-00, dr.ramazanovna@gmail.com,
https://orcid.org/0009-0007-7494-5807
Corresponding author: Mariami G. Kaviladze, mariam-kaviladze@mail.ru

Similar Articles

№6 / 2022
Chernyshova А.L., Коlomiets L.А., Ivanova T.V., Usynin E.A., Afanasyev S.G., Shpileva O.V., Dil O.S., Li A.A., Bochkov Yu.A., Devald E.V., Antipov V.A., Krasilnikov S.E.
The course and outcome of pregnancy in the presence of advanced cervical cancer
№9 / 2024
Zefirova T.P., Sadykova D.A., Dzamukov R.A., Tolibova G.Kh., Gusev V.I., Evsegneeva I.V.
A new perspective on the causes of reproductive failure in women with chronic endometritis
№2 / 2024
Tereschenko I.V.
Kisspeptin in the normal and pathological conditions
№9 / 2023
Levakov S.A., Obukhova E.A., Sheshukova N.A., Dzhafarova M.M., Kaviladze M.G.
Clinical and anamnestic features of diseases of the cervix
№8 / 2022
Yakushevskaya O.V., Babaeva N.A., Yureneva S.V., Ashrafyan L.A.
Impact of menopausal hormone therapy on the development and progression of cervical and endometrial cancers
By continuing to use our site, you consent to the processing of cookies that ensure the proper functioning of the site.