Non-coding RNAs and Other Epigenetic Markers of Cervical Carcinogenesis: New Horizons in Molecular Diagnostics and Prediction of Cervical Cancer
A. G. Sychugov,
Yu. A. Semenov,
E. L. Kazachkov,
I. V. Boyko,
G. V. Sychugov,
A. V. Sherstobitov,
E. A. Kazachkova https://doi.org/10.52420/umj.25.2.92
EDN: TLDKHD
Abstract
Introduction. Currently, cervical cancer (CC) remains a critical issue in oncogynecology. The search for new molecular biomarkers for predicting the occurrence and early diagnosis of CC is an urgent task. In this context, microRNAs (miRNAs) and circular RNAs (circRNAs) are of particular interest.
Materials and methods. An analytical review of contemporary scientific publications (from the last 10 years) from the databases PubMed, Scopus, eLibrary.ru, and Google Scholar has been conducted, focusing on the role of miRNAs and circRNAs in the pathogenesis, diagnosis, and prognosis of cervical intraepithelial neoplasia (CIN) and CC.
Results. Literature data on characteristic patterns of miRNA dysregulation (hyperexpression of miRNA-20a, miRNA-21; hypoexpression of miRNA-23b, miRNA-135a, miRNA-145) at various stages of cervical carcinogenesis associated with human papillomavirus (HPV)-induced oncogenesis have been summarized. Published information on key axes of “circRNA-miRNA-mRNA” regulatory networks mediating essential oncogenic processes has been systematized. Literature data on the significant diagnostic and prognostic potential of miRNA panels (for example, miRNA-20a, miRNA-21, miRNA-23b) have been presented for both tissue samples and liquid cytology materials.
Discussion. The review results demonstrate the evolution of research from studying individual biomarker molecules to a systemic analysis of integral regulatory complexes. The combination of miRNA, circRNA, and epigenetic markers (DNA methylation) analysis within integrative algorithms appears to be the most promising direction for personalizing screening, diagnosis, and prognostic assessment in CC.
About the Authors
A. G. Sychugov
Ural Research Institute for Maternal and Child Care
Russian Federation
Competing Interests:
Russian Federation
Alexander G. Sychugov — Head of the Laboratory of Pathomorphology and Cytodiagnostics
Ekaterinburg
Competing Interests:
The remaining authors declare no obvious or potential conflicts of interest
Yu. A. Semenov
Ural State Medical University
Russian Federation
Competing Interests:
Russian Federation
Yuri A. Semenov — Doctor of Sciences (Medicine), Associate Professor
Ekaterinburg
Competing Interests:
Еditor-in-chief of the Ural Medical Journal
E. L. Kazachkov
South Ural State Medical University;
Chelyabinsk Regional Pathological Anatomy Bureau
Russian Federation
Competing Interests:
Russian Federation
Evgeny L. Kazachkov — Doctor of Sciences (Medicine), Professor, Head of the Department of Pathological Anatomy and Forensic Medicine named after Professor V. L. Kovalenko, South Ural State Medical University; Pathologist, Pathology Department No. 2, Chelyabinsk Regional Pathological Anatomy Bureau
Chelyabinsk
Competing Interests:
Мembers of the editorial board of the Ural Medical Journal; they did not participate in the review of the material or the decision to publish it
I. V. Boyko
Regional Perinatal Center
Russian Federation
Competing Interests:
Russian Federation
Irina V. Boyko — Candidate of Sciences (Medicine), Head of the Consultative and Diagnostic Department
Chelyabinsk
Competing Interests:
The remaining authors declare no obvious or potential conflicts of interest
G. V. Sychugov
South Ural State Medical University;
Chelyabinsk Regional Pathological Anatomy Bureau
Russian Federation
Competing Interests:
Russian Federation
Gleb V. Sychugov — Candidate of Sciences (Medicine), Associate Professor of the Department of Patholog‑ ical Anatomy and Forensic Medicine named after Professor V. L. Kovalenko, South Ural State Medical University; Deputy Chief Physician, Chelyabinsk Regional Pathological Anatomy Bureau
Chelyabinsk
Competing Interests:
The remaining authors declare no obvious or potential conflicts of interest
A. V. Sherstobitov
Ural Research Institute for Maternal and Child Care
Russian Federation
Competing Interests:
Russian Federation
Alexey V. Sherstobitov — Acting Director
Ekaterinburg
Competing Interests:
The remaining authors declare no obvious or potential conflicts of interest
E. A. Kazachkova
South Ural State Medical University
Russian Federation
Competing Interests:
Russian Federation
Ella A. Kazachkova — Doctor of Sciences (Medicine), Professor, Professor of the Department of Obstetrics and Gynecology
Chelyabinsk
Competing Interests:
Мembers of the editorial board of the Ural Medical Journal; they did not participate in the review of the material or the decision to publish it
References
1. Wu J, Jin Q, Zhang Y, Ji Y, Li J, Liu X, et al. Global burden of cervical cancer: Current estimates, temporal trend and future projections based on the GLOBOCAN 2022. Journal of the National Cancer Center. 2025;5(3):322–329. DOI: https://doi.org/10.1016/j.jncc.2024.11.006.
2. Kit OI, Timoshkova MYu, Maksimov AYu, Verenikina EV, Kecheryukova MM, Lukbanova EA. MiRNK expression in patients with malignant and precancerous cervical diseases. Medical News of the North Caucasus. 2020;15(4):519–522. (In Russ.). DOI: https://doi.org/10.14300/mnnc.2020.15122.
3. Marth C, Landoni F, Mahner S, McCormack M, Gonzalez-Martin A, Colombo N; ESMO Guidelines Committee. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2017;28(Suppl 4):iv72–iv83. DOI: https://doi.org/10.1093/annonc/mdx220.
4. Bosch FX, Broker TR, Forman D, Moscicki AB, Gillison ML, Doorbar J, et al. Comprehensive control of human papillomavirus infections and related diseases. Vaccine. 2013;31(Suppl 7):H1–H31. DOI: https://doi.org/10.1016/j.vaccine.2013.10.003.
5. Arkhangelskaya PA, Bakhidze EV, Berlev IV, Samsonov RB, Ivanov MK, Malek AV. MicroRNA, HPV and cervical carcinogenesis: Molecular aspects and prospects for clinical application. Siberian Journal of Oncology. 2016;15(4):88–97. (In Russ.). DOI: https://doi.org/10.21294/1814-4861-2016-15-4-88-97.
6. Robinson EF, Darby JP, Moulder JK. Cervical cancer screening: Missed opportunities in a one-track model. International Journal of Gynecological Cancer. 2023;33(4):646. DOI: https://doi.org/10.1136/ijgc-2023-004311.
7. Williamson AL. The interface between human immunodeficiency virus and human papillomaviruses in heterosexuals in Africa. Journal of Clinical Medicine. 2015;4(4):579–592. DOI: https://doi.org/10.3390/jcm4040579.
8. Medda A, Duca D, Chiocca S. Human papillomavirus and cellular pathways: Hits and targets. Pathogens. 2021;10(3):262. DOI: https://doi.org/10.3390/pathogens10030262.
9. Matos AGM, Silva GEB, Barbosa ES, de Andrade MS, Santos Lages J, Corrêa RGCF, et al. What is the role of circRNAs in the pathogenesis of cervical cancer? A systematic literature review. Frontiers in Genetics. 2024;15:1287869. DOI: https://doi.org/10.3389/fgene.2024.1287869.
10. Cao X, Ma Q, Wang B, Qian Q, Xi Y. Circ-E2F3 promotes cervical cancer progression by inhibiting microRNA 296–5p and increasing STAT3 nuclear translocation. Annals of the New York Academy of Sciences. 2022;1507(1):84–98. DOI: https://doi.org/10.1111/nyas.14653.
11. Zhang X, Yuan Y, Wang X, Wang H, Zhang L, He J. CircWHSC1 (CircNSD2): A novel circular RNA in multiple cancers. Clinical Medicine Insights: Oncology. 2024;18:11795549241254781. DOI: https://doi.org/10.1177/11795549241254781.
12. Dimitriadi TA, Burtsev DV, Dzhenkova EA, Kutilin DS. Micro-RNA as markers of pre-cancer diseases progression in cervical cancer. Modern Problems of Science and Education. 2020;(1):99. (In Russ.). DOI: https://doi.org/10.17513/spno.29529.
13. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. International Journal of Cancer. 2019;144(8):1941–1953. DOI: https://doi.org/10.1002/ijc.31937.
14. Rodríguez AC, Schiffman M, Herrero R, Wacholder S, Hildesheim A, Castle PE, et al. Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. Journal of the National Cancer Institute. 2008;100(7):513–517. DOI: https://doi.org/10.1093/jnci/djn044.
15. Elkin DS, Taubinskaya MI, Elkina NV, Faskhutdinov RS, Fedorova MD, Katargin AN, et al. Diagnostic potential of miRNA 135A1 in human papillomavirus associated cervical lesions. Advances in Molecular Oncology. 2024;11(3):56–67. (In Russ.). DOI: https://doi.org/10.17650/2313-805X-2024-11-3-56-67.
16. Vinokurova SV, Katargin AN. Human papillomavirus and upper respiratory diseases: Head and neck cancer and respiratory papillomatosis. Head and Neck. Russian Journal. 2023;11(1):62–73. (In Russ.). DOI: https://doi.org/10.25792/HN.2023.11.1.62-73.
17. Kamali MJ, Salehi M, Mostafavi M, Morovatshoar R, Akbari M, Latifi N, et al. Hijacking and rewiring of host CircRNA/miRNA/mRNA competitive endogenous RNA (ceRNA) regulatory networks by oncoviruses during development of viral cancers. Reviews in Medical Virology. 2024;34(2):e2530. DOI: https://doi.org/10.1002/rmv.2530.
18. Yang Q, Al-Hendy A. The regulatory functions and the mechanisms of long non-coding RNAs in cervical cancer. Cells. 2022;11(7):1149. DOI: https://doi.org/10.3390/cells11071149.
19. Doorbar J. The human papillomavirus twilight zone — latency, immune control and subclinical infection. Tumour Virus Research. 2023;16:200268. DOI: https://doi.org/10.1016/j.tvr.2023.200268.
20. Cuciniello R, Filosa S, Crispi S. Novel approaches in cancer treatment: Preclinical and clinical development of small non-coding RNA therapeutics. Journal of Experimental & Clinical Cancer Research. 2021;40(1):383. DOI: https://doi.org/10.1186/s13046-021-02193-1.
21. Yeung CL, Tsang TY, Yau PL, Kwok TT. Human papillomavirus type 16 E6 suppresses microRNA 23b expression in human cervical cancer cells through DNA methylation of the host gene C9orf3. Oncotarget. 2017;8(7):12158–12173. DOI: https://doi.org/10.18632/oncotarget.14555.
22. Maksimov AY, Timoshkova MY, Verenikina EV, Lukbanova EA, Kecheryukova MM. Evaluation of the microRNA profile in the cervical epithelium for predicting the development of cervical cancer recurrence. Almanac of Clinical Medicine. 2020;48(5):333–340. (In Russ.). DOI: https://doi.org/10.18786/2072-0505-2020-48-054.
23. Fang QY, Deng QF, Luo J, Zhou CC. MiRNA 20a 5p accelerates the proliferation and invasion of non-small cell lung cancer by targeting and downregulating KLF9. European Review for Medical and Pharmacological Sciences. 2020;24(5):2548–2556. DOI: https://doi.org/10.26355/eur-rev_202003_20522.
24. Zhou W, Xu J, Wang C, Shi D, Yan Q. miR 23b 3p regulates apoptosis and autophagy via suppressing SIRT1 in lens epithelial cells. Journal of Cellular Biochemistry. 2019;120(12):19635–19646. DOI: https://doi.org/10.1002/jcb.29270.
25. Chopjitt P, Pientong C, Bumrungthai S, Kongyingyoes B, Ekalaksananan T. Activities of E6 protein of human papillomavirus 16 Asian variant on miR 21 up-regulation and expression of human immune response genes. Asian Pacific Journal of Cancer Prevention. 2015;16(9):3961–3968. DOI: https://doi.org/10.7314/APJCP.2015.16.9.3961.
26. Kit OI, Maksimov AYu, Timoshkova MYu, Lukbanova EA., Petrusenko NA, Potemkin DS, et al. Diagnostic informative value of liquid-based cytology optimized with genetic methods for the differential diagnosis of precancerous and malignant diseases of the cervix. Research and Practical Medicine Journal. 2021;8(2):12–22. (In Russ.). DOI: https://doi.org/10.17709/2410-1893-2021-8-2-1.
27. Chimitdorzhieva TN, Pisareva LF, Lyakhova NP. Cervical cancer: Incidence and mortality (review). Siberian Scientific Medical Journal. 2017;37(4):85–91. (In Russ.). EDN: https://elibrary.ru/ZFTRIZ.
28. Bierkens M, Krijgsman O, Wilting SM, Bosch L, Jaspers A, Meijer GA, et al. Focal aberrations indicate EYA2 and hsa-miR 375 as oncogene and tumor suppressor in cervical carcinogenesis. Genes, Chromosomes and Cancer. 2013;52(1):56–68. DOI: https://doi.org/10.1002/gcc.22006.
29. Cammarata G, Barraco N, Giusti I, Gristina V, Dolo V, Taverna S. Extracellular vesicles-ceRNAs as ovarian cancer biomarkers: Looking into circRNA-miRNA-mRNA code. Cancers. 2022;14(14):3404. DOI: https://doi.org/10.3390/cancers14143404.
30. Beglyarzade SA, Tamrazov RI, Musaev ER, Wang C. Circular RNA expression profile in cervical cancer and construction of the circular RNA MicroRNA messenger RNA regulatory network. Creative Surgery and Oncology. 2024;14(2):116–126. (In Russ.). DOI: https://doi.org/10.24060/2076-3093-2024-14-2-116-126.
31. Podwika SE, Duska LR. Top advances of the year: Cervical cancer. Cancer. 2023;129(5):657–663. DOI: https://doi.org/10.1002/cncr.34617.
32. Chandrashekar D, Karthikeyan SK, Korla PK, Patel H, Shovon AR, Athar M, et al. UALCAN: An update to the integrated cancer data analysis platform. Neoplasia. 2022;25:18–27. DOI: https://doi.org/10.1016/j.neo.2022.01.001.
33. Sokale IO, Thrift AP, Montealegre J, Adekanmbi V, Chido-Amajuoyi OG, Amuta A, et al. Geographic variation in late-stage cervical cancer diagnosis. JAMA Network Open. 2023;6(11):e2343152. DOI: https://doi.org/10.1001/jamanetworkopen.2023.43152.
34. Pulliero A, Cassatella G, Astuni P, Khalid Z, Fiordoro S, Izzotti A. The role of microRNA expression and DNA methylation in HPV-related cervical cancer: A systematic review. International Journal of Molecular Sciences. 2024;25(23):12714. DOI: https://doi.org/10.3390/ijms252312714.
35. Sammarco ML, Tamburro M, Pulliero A, Izzotti A, Ripabelli G. Human papillomavirus infections, cervical cancer and MicroRNAs: An overview and implications for public health. MicroRNA. 2020;9(3):174–186. DOI: https://doi.org/10.2174/2211536608666191026115045.
36. Lintao RCV, Cando LFT, Perias GAS, Tantengco OAG, Tabios IKB, Velayo CL, et al. Current status of human papillomavirus infection and cervical cancer in the Philippines. Frontiers in Medicine. 2022;9:929062. DOI: https://doi.org/10.3389/fmed.2022.929062.
37. Alimohammadi M, Imani Fooladi AA, Mafi A, Alavioun SM, Cho WC, Reiter RJ, et al. Long noncoding RNAs and HPV-related cervical cancer: Uncovering molecular mechanisms and clinical applications. Translational Oncology. 2025;55:102363. DOI: https://doi.org/10.1016/j.tranon.2025.102363.
38. Giordo R, Ahmadi FAM, Husaini NA, Al-Nuaimi NRAM, Ahmad SMS, Pintus G, et al. microRNA 21 and long non-coding RNAs interplays underlie cancer pathophysiology: A narrative review. Non-coding RNA Research. 2024;9(3):831–852. DOI: https://doi.org/10.1016/j.ncrna.2024.03.013.
39. Boland CR. Non-coding RNA: It’s Not Junk. Digestive Diseases and Sciences. 2017;62(5):1107–1109. DOI: https://doi.org/10.1007/s10620-017-4506-1.
40. Sekulovski S, Trowitzsch S. Transfer RNA processing — from a structural and disease perspective. Biological Chemistry. 2022;403(8–9):749–763. DOI: https://doi.org/10.1515/hsz-2021-0406.
41. Statello L, Guo CJ, Chen LL, Huarte M. Gene regulation by long non-coding RNAs and its biological functions. Nature Reviews Molecular Cell Biology. 2021;22(2):96–118. DOI: https://doi.org/10.1038/s41580-020-00315-9.
42. Gao N, Li Y, Li J, Gao Z, Yang Z, Li Y, et al. Long non-coding RNAs: The regulatory mechanisms, research strategies, and future directions in cancers. Frontiers in Oncology. 2020;10:598817. DOI: https://doi.org/10.3389/fonc.2020.598817.
43. Schmitz SU, Grote P, Herrmann BG. Mechanisms of long noncoding RNA function in development and disease. Cellular and Molecular Life Sciences. 2016;73:2491–2509. DOI: https://doi.org/10.1007/s00018-016-2174-5.
44. Liu Y, Yang Y, Wang X, Yin S, Liang B, Zhang Y, et al. Function of microRNA 124 in the pathogenesis of cancer (review). International Journal of Oncology. 2023;64(1):6. DOI: https://doi.org/10.3892/ijo.2023.5594.
45. Isaac R, Reis FCG, Ying W, Olefsky JM. Exosomes as mediators of intercellular crosstalk in metabolism. Cell Metabolism. 2021;33(9):1744–1762. DOI: https://doi.org/10.1016/j.cmet.2021.08.006.
46. Ma Y, Shen N, Wicha MS, Luo M. The roles of the let 7 family of microRNAs in the regulation of cancer stemness. Cells. 2021;10(9):2415. DOI: https://doi.org/10.3390/cells10092415.
47. Urabe F, Kosaka N, Sawa Y, Yamamoto Y, Ito K, Yamamoto T, et al. miR 26a regulates extracellular vesicle secretion from prostate cancer cells via targeting SHC4, PFDN4, and CHORDC1. Science Advances. 2020;6(18):eaay3051. DOI: https://doi.org/10.1126/sciadv.aay3051.
48. Jiang NJ, Yin YN, Lin J, Li WY, Long DR, Mei L. MicroRNA 21 in gynecological cancers: From molecular pathogenesis to clinical significance. Pathology — Research and Practice. 2023;248:154630. DOI: https://doi.org/10.1016/j.prp.2023.154630.
49. Abdelmaksoud NM, El-Mahdy HA, Ismail A, Elsakka EGE, El-Husseiny AA, Khidr EG, et al. The role of miRNAs in the pathogenesis and therapeutic resistance of endometrial cancer: A spotlight on the convergence of signaling pathways. Pathology — Research and Practice. 2023;241:154245. DOI: https://doi.org/10.1016/j.prp.2023.154411.
50. Olivieri F, Prattichizzo F, Giuliani A, Matacchione G, Rippo MR, Sabbatinelli J, et al. miR 21 and miR 146a: The microRNAs of inflammaging and age-related diseases. Ageing Research Reviews. 2021;70:101374. DOI: https://doi.org/10.1016/j.arr.2021.101374.
51. Shah S, Cheung A, Kutka M, Sheriff M, Boussios S. Epithelial ovarian cancer: Providing evidence of predisposition genes. International Journal of Environmental Research and Public Health. 2022;19(13):8113. DOI: https://doi.org/10.3390/ijerph19138113.
52. Zhou M, Liu L, Wang J, Liu W. The role of long noncoding RNAs in therapeutic resistance in cervical cancer. Frontiers in Cell and Developmental Biology. 2022;10:1060909. DOI: https://doi.org/10.3389/fcell.2022.1060909.
53. Balaji S, Kim U, Muthukkaruppan V, Vanniarajan A. Emerging role of tumor microenvironment derived exosomes in therapeutic resistance and metastasis through epithelial-to-mesenchymal transition. Life Sciences. 2021;280:119750. DOI: https://doi.org/10.1016/j.lfs.2021.119750.
54. Barnestein R, Galland L, Kalfeist L, Ghiringhelli F, Ladoire S, Limagne E. Immunosuppressive tumor microenvironment modulation by chemotherapies and targeted therapies to enhance immunotherapy effectiveness. Oncoimmunology. 2022;11(1):2120676. DOI: https://doi.org/10.1080/2162402X.2022.2120676.
55. Bayik D, Lathia JD. Cancer stem cell-immune cell crosstalk in tumour progression. Nature Reviews Cancer. 2021;21(8):526–536. DOI: https://doi.org/10.1038/s41568-021-00366-w.
56. Li Y, Li C, Liu S, Yang J, Shi L, Yao Y. The associations and roles of microRNA single-nucleotide polymorphisms in cervical cancer. International Journal of Medical Sciences. 2021;18(11):2347–2354. DOI: https://doi.org/10.7150/ijms.57990.
57. Weng Y, Wang B, Zheng L. Association of rs895819 with risk of cervical cancer in Chinese women. Journal of Cancer. 2020;11(21):6286–6287. DOI: https://doi.org/10.7150/jca.46648.
58. Chen G, Zhang M, Zhu J, Chen F, Yu D, Zhang A, et al. Common genetic variants in pre-microRNAs are associated with cervical cancer susceptibility in southern Chinese women. Journal of Cancer. 2020;11(8):2133–2138. DOI: https://doi.org/10.7150/jca.39636.
59. Zhao W, Liu Y, Zhang L, Ding L, Li Y, Zhang H, et al. MicroRNA 154–5p regulates the HPV16 E7 pRb pathway in cervical carcinogenesis by targeting CUL2. Journal of Cancer. 2020;11(18):5379–5389. DOI: https://doi.org/10.7150/jca.45871.
60. Zheng Y, Li X, Jiao Y, Wu C. High-risk human papillomavirus oncogenic E6/E7 mRNAs splicing regulation. Frontiers in Cellular and Infection Microbiology. 2022;12:929666. DOI: https://doi.org/10.3389/fcimb.2022.929666.
Review
For citations:
Sychugov AG, Semenov YA, Kazachkov EL, Boyko IV, Sychugov GV, Sherstobitov AV, Kazachkova EA. Non-coding RNAs and Other Epigenetic Markers of Cervical Carcinogenesis: New Horizons in Molecular Diagnostics and Prediction of Cervical Cancer. Ural Medical Journal. 2026;25(2):92–110. (In Russ.) https://doi.org/10.52420/umj.25.2.92. EDN: TLDKHD
Views:
353
JATS XML
Email this article 