ssmuБюллетень сибирской медициныBulletin of Siberian Medicine1682-03631819-3684Siberian State Medical University, the Ministry of Healthcare of the Russian Federation10.20538/1682-0363-2023-2-145-155ssmu-5231Research ArticleОБЗОРЫ И ЛЕКЦИИREVIEW AND LECTURESCовременные представления о цервикальном канцерогенезеModern concepts in cervical carcinogenesishttps://orcid.org/0000-0003-1145-3710НаумоваЛ. А.NaumovaL. A.

Наумова Людмила Алексеевна – д-р мед. наук, профессор кафедры патофизиологии и общей патологии, Медицинский институт, 

628412, Ханты-Мансийский автономный округ (ХМАО) – Югра, г. Сургут, ул. Ленина, 1

1, Lenina Str., Surgut, Khanty-Mansiysk Autonomous Area – Yugra, 628412

naumovala@yandex.ruhttps://orcid.org/0000-0001-8362-0608СтародумоваВ. А.StarodumovaV. A.

Cтародумова Валентина Анатольевна – аспирант, кафедра патофизиологии и общей патологии, Медицинский институт,

628412, Ханты-Мансийский автономный округ (ХМАО) – Югра, г. Сургут, ул. Ленина, 1

1, Lenina Str., Surgut, Khanty-Mansiysk Autonomous Area – Yugra, 628412

starodumovav@list.ruСургутский государственный университет (СурГУ)РоссияSurgut State UniversityRussian Federation202310072023222145155Copyright © Наумова Л.А., Стародумова В.А., 20232023Наумова Л.А., Стародумова В.А.Naumova L.A., Starodumova V.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://bulletin.ssmu.ru/jour/article/view/5231

Рассматриваются современные представления о цервикальном канцерогенезе как многостадийном процессе мультифакторного генеза. В настоящее время представления о патогенезе рака шейки матки (РШМ) базируются не только на понимании роли в этом процессе вируса папилломы человека (ВПЧ) высокого онкогенного риска и накоплении обусловленных им генетических изменений, но и формировании сложного интерактома ВПЧ, или сети межмолекулярных взаимодействий онкобелков ВПЧ с белками клетки-хозяина. Также в процессе канцерогенеза принимают участие эпигенетические модификации широкого спектра и, прежде всего, нарушения регуляторной функции микроРНК. Важное место в представлениях о цервикальном канцерогенезе занимает сформулированная в последние годы концепция раковых стволовых клеток (CSCs), с которой тесно связано объяснение рецидивов заболевания и устойчивости к лечению, а также понимание новых подходов к лечению. Перспективным объектом для исследования становится также цервиковагинальный микробиом и цервикальное микроокружение, ответственные за естественный клиренс ВПЧ, регрессию эпителиальных повреждений и моделирование иммунного ответа.

Цель обзора – изложение актуальной информации о важнейших механизмах цервикального канцерогенеза, а также новых подходах к лечению РШМ, базирующихся в частности на использовании знаний о регуляторных микроРНК, маркерах CSCs и состоянии цервиковагинальной микробиоты.

The article discusses modern ideas about cervical carcinogenesis as a multi-stage process of multifactorial genesis. Currently, ideas about the pathogenesis of cervical cancer (CC) are based not only on understanding the role of high-risk oncogenic human papillomavirus (HPV) in this process and accumulation of genetic changes caused by it, but also on formation of a complex HPV interactome, or a network of intermolecular interactions of HPV oncoproteins with host cell proteins. Carcinogenesis also involves a wide range of epigenetic events and, above all, impairment of the regulatory function of miRNAs. An important role in cervical carcinogenesis is attributed to the concept of cancer stem cells (CSCs) formulated in recent years, which is closely related to the explanation of disease recurrence and treatment resistance, as well as to new approaches to treatment. The cervicovaginal microbiome and cervical microenvironment, which are responsible for natural clearance of HPV, regression of epithelial lesions, and modeling of the immune response, are becoming promising objects for research.

The aim of the review was to present up-to-date information on the most important mechanisms of cervical carcinogenesis, as well as on new approaches to the treatment of CC, based, in particular, on the use of knowledge about regulatory miRNAs, CSC markers, and the state of the cervicovaginal microbiota.

цервикальный канцерогенезгеномика рака шейки маткимикроРНКраковые стволовые клеткимикробиотаcervical carcinogenesiscervical cancer genomicsmiRNAcancer stem cellsmicrobiotaReferencesWilailak S., Kengsakil M., Kehoe S. Worldwide initiatives to eliminate cervical cancer. Int. J. Gynecol. Obstet. 2021;155(1):102–106. DOI: 10.1002/ijgo.13879.Wilailak S., Kengsakil M., Kehoe S. Worldwide initiatives to eliminate cervical cancer. Int. J. Gynecol. Obstet. 2021;155(1):102–106. DOI: 10.1002/ijgo.13879.Bhatla N., Aoki D., Sharma D.N., Sankaranarayanan R. Cancer of the cervix uteri. Int. J. Gynaecol. Obstet. 2018;143(2):22– 36. DOI: 10.1002/ijgo.12611.Bhatla N., Aoki D., Sharma D.N., Sankaranarayanan R. Cancer of the cervix uteri. Int. J. Gynaecol. Obstet. 2018;143(2):22– 36. DOI: 10.1002/ijgo.12611.Lin M., Ye M., Zhu X. Recent advances on the molecular mechanism of cervical carcinogenesis based on systems biology technologies. Comput. Struct. Biotechnol. J. 2019;17:241– 250. DOI: 10.1016/j.csbj.2019.02.001.Lin M., Ye M., Zhu X. Recent advances on the molecular mechanism of cervical carcinogenesis based on systems biology technologies. Comput. Struct. Biotechnol. J. 2019;17:241– 250. DOI: 10.1016/j.csbj.2019.02.001.Fiore R.D., Suleiman S., Drago-Ferrante R., Subbannayya Y., Pentimalli F., Giordano A. et al. Cancer Stem Cells and Their Possible Implications in Cervical Cancer: A Short Review. Int. J. Mol. Sci. 2022;23(9):5167. DOI: 10.3390/ijms23095167.Fiore R.D., Suleiman S., Drago-Ferrante R., Subbannayya Y., Pentimalli F., Giordano A. et al. Cancer Stem Cells and Their Possible Implications in Cervical Cancer: A Short Review. Int. J. Mol. Sci. 2022;23(9):5167. DOI: 10.3390/ijms23095167.Mendoza-Almanza G., Ortíz-Sánchez E., Rocha-Zavaleta L., Rivas-Santiago C., Esparza-Ibarra E., Olmos J. Cervical cancer stem cells and other leading factors associated with cervical cancer development. Oncol. Lett. 2019;18(4):3423–3432. DOI: 10.3892/ol.2019.10718.Mendoza-Almanza G., Ortíz-Sánchez E., Rocha-Zavaleta L., Rivas-Santiago C., Esparza-Ibarra E., Olmos J. Cervical cancer stem cells and other leading factors associated with cervical cancer development. Oncol. Lett. 2019;18(4):3423–3432. DOI: 10.3892/ol.2019.10718.Guo L., Hua K. Cervical cancer: emerging immune landscape and treatment. Onco. Targets Ther. 2020;12(13):8037–8047. DOI: 10.2147/OTT.S264312.Guo L., Hua K. Cervical cancer: emerging immune landscape and treatment. Onco. Targets Ther. 2020;12(13):8037–8047. DOI: 10.2147/OTT.S264312.Dai W., Du H., Li S., Wu R. Cervicovaginal microbiome factors in clearance of human papillomavirus Infection. Front. Oncol. 2021;11:722639. DOI: 10.3389/fonc.2021.722639.Dai W., Du H., Li S., Wu R. Cervicovaginal microbiome factors in clearance of human papillomavirus Infection. Front. Oncol. 2021;11:722639. DOI: 10.3389/fonc.2021.722639.Chhabra R. Cervical cancer stem cells: opportunities and challenges. J. Cancer Res. Clin. Oncol. 2015;141(11):1889–1897. DOI: 10.1007/s00432-014-1905-y.Chhabra R. Cervical cancer stem cells: opportunities and challenges. J. Cancer Res. Clin. Oncol. 2015;141(11):1889–1897. DOI: 10.1007/s00432-014-1905-y.Huang R., Rofstad E.K. Cancer stem cells (CSCs), cervical CSCs and targeted therapies. Oncotarget. 2017;8(21):35351– 35367. DOI: 10.18632/oncotarget.10169Huang R., Rofstad E.K. Cancer stem cells (CSCs), cervical CSCs and targeted therapies. Oncotarget. 2017;8(21):35351– 35367. DOI: 10.18632/oncotarget.10169Zhao Z., Wang Y., Wu Y., Li D., Zhang T., Ma Y. et al. Single-cell analysis defines the lineage plasticity of stem cells in cervix epithelium. Cell Regen. 2021;10(1):36. DOI: 10.1186/s13619-021-00096-2.Zhao Z., Wang Y., Wu Y., Li D., Zhang T., Ma Y. et al. Single-cell analysis defines the lineage plasticity of stem cells in cervix epithelium. Cell Regen. 2021;10(1):36. DOI: 10.1186/s13619-021-00096-2.Ortiz-Sánchez E., Santiago-López L., Cruz-Domínguez V.B., Toledo-Guzmán M.E., Hernandez-Gueto D., Muñiz-Hernández S. et al. Characterization of cervical cancer stem celllike cells: phenotiping, stemness, and human papilloma virus co-receptor expression. Oncotarget. 2016;7(22):31943– 31954. DOI: 10.18632/oncotarget.8218.Ortiz-Sánchez E., Santiago-López L., Cruz-Domínguez V.B., Toledo-Guzmán M.E., Hernandez-Gueto D., Muñiz-Hernández S. et al. Characterization of cervical cancer stem celllike cells: phenotiping, stemness, and human papilloma virus co-receptor expression. Oncotarget. 2016;7(22):31943– 31954. DOI: 10.18632/oncotarget.8218.Senapati R., Senapati N.N., Dwibedi B. Molecular mechanisms of HPV mediated neoplastic progression. Infect. Agent. Cancer. 2016;11(1):59. DOI: 10.1186/s13027-016-0107-4.Senapati R., Senapati N.N., Dwibedi B. Molecular mechanisms of HPV mediated neoplastic progression. Infect. Agent. Cancer. 2016;11(1):59. DOI: 10.1186/s13027-016-0107-4.Soto D., Song C., McLaughlin-Drubin M.E. Epigenetic alterations in human papillomavirus-associated cancers. Viruses. 2017;9(9):248. DOI: 10.3390/v9090248.Soto D., Song C., McLaughlin-Drubin M.E. Epigenetic alterations in human papillomavirus-associated cancers. Viruses. 2017;9(9):248. DOI: 10.3390/v9090248.Da Silva M.L.R., De Albuquerque B.H.D.R., Allyrio T.A.M.F., De Almeida V.D., Cobucci R.N.O., Bezerra F.L. et al. The role of HPV-induced epigenetic changes in cervical carcinogenesis (Review). Biomed. Rep. 202115(1):60. DOI: 10.3892/br.2021.1436.Da Silva M.L.R., De Albuquerque B.H.D.R., Allyrio T.A.M.F., De Almeida V.D., Cobucci R.N.O., Bezerra F.L. et al. The role of HPV-induced epigenetic changes in cervical carcinogenesis (Review). Biomed. Rep. 202115(1):60. DOI: 10.3892/br.2021.1436.Bañuelos-Villegas E.G., Pérez-yPérez M.F., Alvarez-Salas L.M. Cervical cancer, papillomavirus, and miRNA dysfunction. Front. Mol. Biosci. 2021;8:758337. DOI: 10.3389/fmolb.2021.758337.Bañuelos-Villegas E.G., Pérez-yPérez M.F., Alvarez-Salas L.M. Cervical cancer, papillomavirus, and miRNA dysfunction. Front. Mol. Biosci. 2021;8:758337. DOI: 10.3389/fmolb.2021.758337.Castanheira C.P., Sallas M.L., Nunes R.A.L., Lorenzi N.P.C., Termini L. Microbiome and cervical cancer. Pathobiology. 2021;88(2):187–197. DOI: 10.1159/000511477.Castanheira C.P., Sallas M.L., Nunes R.A.L., Lorenzi N.P.C., Termini L. Microbiome and cervical cancer. Pathobiology. 2021;88(2):187–197. DOI: 10.1159/000511477.Lee S.A., Baik S., Chung S.H. Functional roles of female sex hormones and their nuclear receptors in cervical cancer. Essays Biochem. 2021;65(6):941–950. DOI: 10.1042/EBC20200175.Lee S.A., Baik S., Chung S.H. Functional roles of female sex hormones and their nuclear receptors in cervical cancer. Essays Biochem. 2021;65(6):941–950. DOI: 10.1042/EBC20200175.Baik S., Mehta F.F., Unsal E., Park Y., Chung S.H. Estrogen inhibits epithelial progesterone receptor-dependent progestin therapy efficacy in a mouse model of cervical cancer. Am. J. Pathol. 2022;192(2):353–360. DOI: 10.1016/j.ajpath.2021.10.008.Baik S., Mehta F.F., Unsal E., Park Y., Chung S.H. Estrogen inhibits epithelial progesterone receptor-dependent progestin therapy efficacy in a mouse model of cervical cancer. Am. J. Pathol. 2022;192(2):353–360. DOI: 10.1016/j.ajpath.2021.10.008.Klein C., Gonzalez D., Samwel K., Kahesa C., Mwaiselage J., Aluthge N. et al. Relationship between the Cervical Microbiome, HIV Status, and Precancerous Lesions. mBio. 2019; 10(1):e02785-18. DOI: 10.1128/mBio.02785-18.Klein C., Gonzalez D., Samwel K., Kahesa C., Mwaiselage J., Aluthge N. et al. Relationship between the Cervical Microbiome, HIV Status, and Precancerous Lesions. mBio. 2019; 10(1):e02785-18. DOI: 10.1128/mBio.02785-18.Manzanares-Leal G.L., Coronel-Martínez J.A., Rodríguez-Morales M., Rangel-Cuevas I., Bustamante-Montes L.P., Sandoval-Trujillo H. et al. Preliminary identification of the aerobic cervicovaginal microbiota in Mexican women with cervical cancer as the first step towards metagenomic studies. Front. Cell Infect. Microbiol. 2022;12:838491. DOI: 10.3389/fcimb.2022.838491.Manzanares-Leal G.L., Coronel-Martínez J.A., Rodríguez-Morales M., Rangel-Cuevas I., Bustamante-Montes L.P., Sandoval-Trujillo H. et al. Preliminary identification of the aerobic cervicovaginal microbiota in Mexican women with cervical cancer as the first step towards metagenomic studies. Front. Cell Infect. Microbiol. 2022;12:838491. DOI: 10.3389/fcimb.2022.838491.Martinez-Rodriduez F., Limones-Gonzalez J.E., Mendoza-Almanza B., Esparza-Ibarra El., Gallegos-Flores P.I., Ayla-Lujan J.A. et al. Understanding cervical cancer trough proteomics. Cells. 2021;10(8):1854. DOI: 10.3390/cells10081854.Martinez-Rodriduez F., Limones-Gonzalez J.E., Mendoza-Almanza B., Esparza-Ibarra El., Gallegos-Flores P.I., Ayla-Lujan J.A. et al. Understanding cervical cancer trough proteomics. Cells. 2021;10(8):1854. DOI: 10.3390/cells10081854.Łaniewski P., Ilhan Z.E., Herbst-Kralovetz M.M. The microbiome and gynaecological cancer development, prevention and therapy. Nat. Rev. Urol. 2020;17(4):232–250. DOI: 10.1038/s41585-020-0286-z.Łaniewski P., Ilhan Z.E., Herbst-Kralovetz M.M. The microbiome and gynaecological cancer development, prevention and therapy. Nat. Rev. Urol. 2020;17(4):232–250. DOI: 10.1038/s41585-020-0286-z.Revathidevi S., Murugan A.K., Nakaoka H., Inoue I., Munirajan A.K. APOBEC: A molecular driver in cervical cancer pathogenesis. Cancer Lett. 2021;496:104–116. DOI: 10.1016/j.canlet.2020.10.004.Revathidevi S., Murugan A.K., Nakaoka H., Inoue I., Munirajan A.K. APOBEC: A molecular driver in cervical cancer pathogenesis. Cancer Lett. 2021;496:104–116. DOI: 10.1016/j.canlet.2020.10.004.Kamal M., Lameiras S., Deloger M., Morel A., Vacher S., Lecerf C. et al. Human papilloma virus (HPV) integration signature in Cervical Cancer: identification of MACROD2 gene as HPV hot spot integration site. Br. J. Cancer. 2021;124(4):777–785. DOI: 10.1038/s41416-020-01153-4.Kamal M., Lameiras S., Deloger M., Morel A., Vacher S., Lecerf C. et al. Human papilloma virus (HPV) integration signature in Cervical Cancer: identification of MACROD2 gene as HPV hot spot integration site. Br. J. Cancer. 2021;124(4):777–785. DOI: 10.1038/s41416-020-01153-4.Salvesen H.B. The cancer genome atlas research network. Integrated genomic and molecular characterization of cervical cancer. Nature. 2017;543(7645):378–384. DOI: 10.1038/nature21386.Salvesen H.B. The cancer genome atlas research network. Integrated genomic and molecular characterization of cervical cancer. Nature. 2017;543(7645):378–384. DOI: 10.1038/nature21386.Organista-Nava J., Gómez-Gómez Y., Garibay-Cerdenares O.L., Leyva-Vázquez M.A., Illades-Aguiar B. Cervical cancer stem cell-associated genes: prognostic implications in cervical cancer. Oncol. Lett. 2019;18(1):7–14. DOI: 10.3892/ol.2019.10307.Organista-Nava J., Gómez-Gómez Y., Garibay-Cerdenares O.L., Leyva-Vázquez M.A., Illades-Aguiar B. Cervical cancer stem cell-associated genes: prognostic implications in cervical cancer. Oncol. Lett. 2019;18(1):7–14. DOI: 10.3892/ol.2019.10307.Кечерюкова М.М., Снежко А.В., Вереникина Е.В., Меньшенинина А.П., Адамян М.Л., Арджа А.Ю. и др. Комплексная молекулярная характеристика рака шейки матки: маркеры метастазирования. Современные проблемы науки и образования. 2020;2. URL:https://science-education.ru/ru/article/view?id=29769 (дата обращения: 23.09.2021).Кечерюкова М.М., Снежко А.В., Вереникина Е.В., Меньшенинина А.П., Адамян М.Л., Арджа А.Ю. и др. Комплексная молекулярная характеристика рака шейки матки: маркеры метастазирования. Современные проблемы науки и образования. 2020;2. URL:https://science-education.ru/ru/article/view?id=29769 (дата обращения: 23.09.2021).Yu X., Xu J., Xu D., Bi X., Wang H., Lu Y. et al. Comprehensive analysis of the carcinogenic process, tumor microenvironment, and drug response in HPV-positive cancers. Front. Oncol. 2022;12:842060. DOI: 10.3389/fonc.2022.842060.Yu X., Xu J., Xu D., Bi X., Wang H., Lu Y. et al. Comprehensive analysis of the carcinogenic process, tumor microenvironment, and drug response in HPV-positive cancers. Front. Oncol. 2022;12:842060. DOI: 10.3389/fonc.2022.842060.Olusola P., Banerjee H.N., Philley J.V., Santanu Dasgupta S. Human papilloma virus-associated cervical cancer and health disparities. Cells. 2019;8(6):622. DOI: 10.3390/cells8060622.Olusola P., Banerjee H.N., Philley J.V., Santanu Dasgupta S. Human papilloma virus-associated cervical cancer and health disparities. Cells. 2019;8(6):622. DOI: 10.3390/cells8060622.Mens M.M.J., Ghanbari M. Cell cycle regulation of stem cells by microRNAs. Stem. Cell Rev. Rep. 2018;14(3):309–322. DOI: 10.1007/s12015-018-9808-y.Mens M.M.J., Ghanbari M. Cell cycle regulation of stem cells by microRNAs. Stem. Cell Rev. Rep. 2018;14(3):309–322. DOI: 10.1007/s12015-018-9808-y.Li Y., Tollefsbol T.O. Age-related epigenetic drift and phenotypic plasticity loss: implications in prevention of age-related human diseases. Epigenomics. 2016;8(12):1637–1651. DOI: 10.2217/epi-2016-0078.Li Y., Tollefsbol T.O. Age-related epigenetic drift and phenotypic plasticity loss: implications in prevention of age-related human diseases. Epigenomics. 2016;8(12):1637–1651. DOI: 10.2217/epi-2016-0078.Shen S., Zhang S., Liu P., Wang J., Du H. Potential role of microRNAs in the treatment and diagnosis of cervical cancer. Cancer Genet. 2020;248–249:25–30. DOI: 10.1016/j.cancergen.2020.09.003.Shen S., Zhang S., Liu P., Wang J., Du H. Potential role of microRNAs in the treatment and diagnosis of cervical cancer. Cancer Genet. 2020;248–249:25–30. DOI: 10.1016/j.cancergen.2020.09.003.Causin R.L., Silva L.S., Evangelista A.F., Leal L.F., Souza K.C.B., Pessôa-Pereira D. et al. MicroRNA biomarkers of high-grade cervical intraepithelial neoplasia in liquid biopsy. Biomed Res. Int. 2021;2021:6650966. DOI: 10.1155/2021/6650966.Causin R.L., Silva L.S., Evangelista A.F., Leal L.F., Souza K.C.B., Pessôa-Pereira D. et al. MicroRNA biomarkers of high-grade cervical intraepithelial neoplasia in liquid biopsy. Biomed Res. Int. 2021;2021:6650966. DOI: 10.1155/2021/6650966.Zheng M., Hou L., Ma Y., Zhou L., Wang F., Cheng B. et al. Exosomal let-7d-3p and miR-30d-5p as diagnostic biomarkers for non-invasive screening of cervical cancer and its precursors. Mol. Cancer. 2019;18(1):76. DOI: 10.1186/s12943-019-0999-x.Zheng M., Hou L., Ma Y., Zhou L., Wang F., Cheng B. et al. Exosomal let-7d-3p and miR-30d-5p as diagnostic biomarkers for non-invasive screening of cervical cancer and its precursors. Mol. Cancer. 2019;18(1):76. DOI: 10.1186/s12943-019-0999-x.Babion I., Jaspers A., van Splunter A.P., van der Hoorn I.A.E., Wilting S.M., Steenbergen R.D.M. miR-9-5p exerts a dual role in cervical cancer and targets transcription factor TWIST1. Cells. 2019;9(1):65. DOI: 10.3390/cells9010065.Babion I., Jaspers A., van Splunter A.P., van der Hoorn I.A.E., Wilting S.M., Steenbergen R.D.M. miR-9-5p exerts a dual role in cervical cancer and targets transcription factor TWIST1. Cells. 2019;9(1):65. DOI: 10.3390/cells9010065.Babion I., Miok V., Jaspers A., Huseinovic A., Steenbergen R.D.M., van Wieringen W.N., Wilting S.M. Identification of deregulated pathways, key regulators, and novel miRNA-mRNA interactions in HPV-mediated transformation. Cancers (Basel). 2020;12(3):700. DOI: 10.3390/cancers12030700.Babion I., Miok V., Jaspers A., Huseinovic A., Steenbergen R.D.M., van Wieringen W.N., Wilting S.M. Identification of deregulated pathways, key regulators, and novel miRNA-mRNA interactions in HPV-mediated transformation. Cancers (Basel). 2020;12(3):700. DOI: 10.3390/cancers12030700.Zhao Z., Wang Y., Wu Y., Li D., Zhang T., Ma Y. et al. Single-cell analysis defines the lineage plasticity of stem cells in cervix epithelium. Cell Regen. 2021;10(1):36. DOI: 10.1186/s13619-021-00096-2.Zhao Z., Wang Y., Wu Y., Li D., Zhang T., Ma Y. et al. Single-cell analysis defines the lineage plasticity of stem cells in cervix epithelium. Cell Regen. 2021;10(1):36. DOI: 10.1186/s13619-021-00096-2.Lim J.R., Mouawad J., Gorton O.K., Bubb W.A., Kwan A.H. Cancer stem cell characteristics and their potential as therapeutic targets. Med. Oncol. 2021;38(7):76. DOI: 10.1007/s12032-021-01524-8.Lim J.R., Mouawad J., Gorton O.K., Bubb W.A., Kwan A.H. Cancer stem cell characteristics and their potential as therapeutic targets. Med. Oncol. 2021;38(7):76. DOI: 10.1007/s12032-021-01524-8.Oshimori N. Cancer stem cells and their niche in the progression of squamous cell carcinoma. Cancer Sci. 2020;111(11):3985– 3992. DOI: 10.1111/cas.14639.Oshimori N. Cancer stem cells and their niche in the progression of squamous cell carcinoma. Cancer Sci. 2020;111(11):3985– 3992. DOI: 10.1111/cas.14639.Sudhalkar N., Rathod N.P., Mathews A., Chopra S., Sriram H., Shrivastava S.K. et al. Potential role of cancer stem cells as biomarkers and therapeutic targets in cervical cancer. Stem. Cell Rev. Rep. 2018;14(3):309–322. DOI: 10.1007/s12015-018-9808-y.Sudhalkar N., Rathod N.P., Mathews A., Chopra S., Sriram H., Shrivastava S.K. et al. Potential role of cancer stem cells as biomarkers and therapeutic targets in cervical cancer. Stem. Cell Rev. Rep. 2018;14(3):309–322. DOI: 10.1007/s12015-018-9808-y.Campo L., Zhang C., Breuer E.-K. EMT-inducing molecular factors in gynecological cancer. Biomad. Res. Int. 2015;2015:420891. DOI: 10.1155/2015/420891.Campo L., Zhang C., Breuer E.-K. EMT-inducing molecular factors in gynecological cancer. Biomad. Res. Int. 2015;2015:420891. DOI: 10.1155/2015/420891.Gonzalez D.M., Medici D. Signaling mechanisms of the epithelial–mesenchymal transition. Science Signaling. 2014;7(344):re8. DOI: 10.1126/scisignal.2005189.Gonzalez D.M., Medici D. Signaling mechanisms of the epithelial–mesenchymal transition. Science Signaling. 2014;7(344):re8. DOI: 10.1126/scisignal.2005189.Ye X., Weinberg R.A. Epithelial–mesenchymal plasticity: a central regulator of cancer progression. Trends Cell Biol. 2015;25(11):675–686. DOI: 10.1016/j.tcb.2015.07.012.Ye X., Weinberg R.A. Epithelial–mesenchymal plasticity: a central regulator of cancer progression. Trends Cell Biol. 2015;25(11):675–686. DOI: 10.1016/j.tcb.2015.07.012.Tango C.N., Seo S.S., Kwon M. et al. Taxonomic and functional differences in cervical microbiome associated with cervical cancer development. Sci Rep. 2020;10(1):9720. DOI: 10.1038/s41598-020-66607-4.Tango C.N., Seo S.S., Kwon M. et al. Taxonomic and functional differences in cervical microbiome associated with cervical cancer development. Sci Rep. 2020;10(1):9720. DOI: 10.1038/s41598-020-66607-4.Kaelin E.A., Skidmore P.T., Łaniewski P., Holland L.A., Chase D.M., Herbst-Kralovetz M.M. et al. Cervicovaginal DNA virome alterations are associated with genital inflammation and microbiota composition. mSystems. 2022;7(2):e0006422. DOI: 10.1128/msystems.00064-22.Kaelin E.A., Skidmore P.T., Łaniewski P., Holland L.A., Chase D.M., Herbst-Kralovetz M.M. et al. Cervicovaginal DNA virome alterations are associated with genital inflammation and microbiota composition. mSystems. 2022;7(2):e0006422. DOI: 10.1128/msystems.00064-22.Muntinga C.L.P., Vos van Steenwijk P.J., Bekkers R.L.M., van Esch E.M.G. Importance of the immune microenvironment in the spontaneous regression of cervical squamous intraepithelial lesions (СSIL) and implications for immunotherapy. J. Clin. Med. 2022;11(5):1432. DOI: 10.3390/jcm11051432.Muntinga C.L.P., Vos van Steenwijk P.J., Bekkers R.L.M., van Esch E.M.G. Importance of the immune microenvironment in the spontaneous regression of cervical squamous intraepithelial lesions (СSIL) and implications for immunotherapy. J. Clin. Med. 2022;11(5):1432. DOI: 10.3390/jcm11051432.Lin W., Zhang Q., Chen Y., Dong B., Xue H., Lei H. et al. Changes of the vaginal microbiota in HPV infection and cervical intraepithelial neoplasia: a cross-sectional analysis. Sci. Rep. 2022;12(1):2812. DOI: 10.1038/s41598-022-06731-5.Lin W., Zhang Q., Chen Y., Dong B., Xue H., Lei H. et al. Changes of the vaginal microbiota in HPV infection and cervical intraepithelial neoplasia: a cross-sectional analysis. Sci. Rep. 2022;12(1):2812. DOI: 10.1038/s41598-022-06731-5.Bokulich N.A., Łaniewski P., Adamov A., Chase D.M., Caporaso J.G., Herbst-Kralovetz M.M. Multi-omics data integration reveals metabolome as the top predictor of the cervicovaginal microenvironment. PLoS Comput. Biol. 2022;18(2):e1009876. DOI: 10.1371/journal.pcbi.1009876.Bokulich N.A., Łaniewski P., Adamov A., Chase D.M., Caporaso J.G., Herbst-Kralovetz M.M. Multi-omics data integration reveals metabolome as the top predictor of the cervicovaginal microenvironment. PLoS Comput. Biol. 2022;18(2):e1009876. DOI: 10.1371/journal.pcbi.1009876.Curty G., de Carvalho P.S., Soares M.A. The role of the cervicovaginal microbiome on the genesis and as a biomarker of premalignant cervical intraepithelial neoplasia and invasive cervical cancer. Int. J. Mol. Sci. 2019;21(1):222. DOI: 10.3390/ijms21010222.Curty G., de Carvalho P.S., Soares M.A. The role of the cervicovaginal microbiome on the genesis and as a biomarker of premalignant cervical intraepithelial neoplasia and invasive cervical cancer. Int. J. Mol. Sci. 2019;21(1):222. DOI: 10.3390/ijms21010222.Yang L., Yang Y., Meng M., Wang W., He S., Zhao Y. et al. Identification of prognosis-related genes in the cervical cancer immune microenvironment. Gene. 2021;766:145119. DOI: 10.1016/j.gene.2020.145119.Yang L., Yang Y., Meng M., Wang W., He S., Zhao Y. et al. Identification of prognosis-related genes in the cervical cancer immune microenvironment. Gene. 2021;766:145119. DOI: 10.1016/j.gene.2020.145119.

The authors declare that there are no conflicts of interest present.