oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2022-21-2-130-142oncotomsk-2098Research ArticleОБЗОРЫREVIEWSМетилирование генов р53-респонзивных онкосупрессорных микроРНК при гемобластозахMethylation of p53-responsive oncosuppressive microRNA genes in hemoblastosishttps://orcid.org/0000-0001-7542-7285ВоропаеваЕ. Н.VoropaevaE. N.

доктор медицинских наук, старший научный сотрудник лаборатории молекулярно-генетических исследований терапевтических заболеваний

SPINкод: 4424-2094. Researcher ID (WOS): A-5360-2014. Author ID (Scopus): 36020818100

Россия, 630089, г. Новосибирск, ул. Б. Богаткова, 175/1 

MD, DSc, Senior Researcher, Laboratory of Molecular Genetic Studies of Therapeutic Diseases

Researcher ID (WOS): A-5360-2014. Author ID (Scopus): 36020818100 

175/1, Boris Bogatkov st., 630089, Novosibirsk, Russia 

vena.81@mail.ruhttps://orcid.org/0000-0002-1261-5470ПоспеловаТ. И.PospelovaT. I.

доктор медицинских наук, профессор, заведующая кафедрой терапии, гематологии и трансфузиологии ФПК и ППВ

Author ID (Scopus): 7005792562

Россия, 630091, г. Новосибирск, ул. Красный проспект, 52 

MD, Professor, Head of the Department of Therapy, Hematology and Transfusiology

Author ID (Scopus): 7005792562 

52, Red Ave., 630091, Novosibirsk, Russia

https://orcid.org/0000-0003-4584-658XБерезинаО. В.BerezinaO. V.

кандидат медицинских наук, ассистент кафедры терапии, гематологии и трансфузиологии ФПК и ППВ

SPIN-код: 8681-4310. Researcher ID (WOS): AAK-3117-2020. Author ID (Scopus): 36605828400

Россия, 630091, г. Новосибирск, ул. Красный проспект, 52 

MD, PhD, Assistant, Department of Therapy, Hematology and Transfusiology

Researcher ID (WOS): AAK-3117-2020. Author ID (Scopus): 36605828400 

52, Red Ave., 630091, Novosibirsk, Russia

https://orcid.org/0000-0002-1301-5944ЧуркинаМ. И.ChurkinaM. I.

аспирант кафедры терапии, гематологии и трансфузиологии ФПК и ППВ

SPIN-код: 7455-5993. Researcher ID (WOS): AAН-6058-2021. Author ID (Scopus): 57219706690

Россия, 630091, г. Новосибирск, ул. Красный проспект, 52 

MD, Postgraduate, Department of Therapy, Hematology and Transfusiology

Researcher ID (WOS): AAН-6058-2021. Author ID (Scopus): 57219706690 

52, Red Ave., 630091, Novosibirsk, Russia

https://orcid.org/0000-0003-1547-624XГуражеваА. А.GurazhevaA. A.

младший научный сотрудник лаборатории молекулярно-генетических методов исследования терапевтических заболеваний  

Россия, 630089, г. Новосибирск, ул. Б. Богаткова, 175/1 

Junior Researcher, Laboratory of Molecular Genetic Studies of Therapeutic Diseases 

175/1, Boris Bogatkov st., 630089, Novosibirsk, Russia 

https://orcid.org/0000-0002-7165-4496МаксимовВ. Н.MaksimovV. N.

доктор медицинских наук, профессор, заведующий лабораторией молекулярно-генетических методов исследования терапевтических заболеваний

SPIN-код: 9953-7867. Researcher ID (WOS): H-7676-2012. Author ID (Scopus): 7202540327

Россия, 630089, г. Новосибирск, ул. Б. Богаткова, 175/1 

MD, Professor, Head of the Laboratory of Molecular-genetic Methods for the Study of Therapeutic Diseases

Researcher ID (WOS): H-7676-2012. Author ID (Scopus): 7202540327 

175/1, Boris Bogatkov st., 630089, Novosibirsk, Russia 

НИИ терапии и профилактической медицины – филиал ФГБНУ «Федеральный исследовательский центр Институт цитологии и генетики СО РАН»РоссияResearch Institute of Therapy and Preventive Medicine – Branch of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of SciencesRussian FederationФГБОУ ВО «Новосибирский государственный медицинский университет» Минздрава РоссииРоссияNovosibirsk State Medical University of the Ministry of Health of RussiaRussian Federation202208052022212130142Copyright © Воропаева Е.Н., Поспелова Т.И., Березина О.В., Чуркина М.И., Гуражева А.А., Максимов В.Н., 20222022Воропаева Е.Н., Поспелова Т.И., Березина О.В., Чуркина М.И., Гуражева А.А., Максимов В.Н.Voropaeva E.N., Pospelova T.I., Berezina O.V., Churkina M.I., Gurazheva A.A., Maksimov V.N.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/2098

Цель исследования – представить современные данные о частоте и значении метилирования генов ряда р53-респонзивных онкосупрессорных микроРНК при опухолевых заболеваниях системы крови.

Материал и методы

Материал и методы. Проведен поиск доступных литературных источников, опубликованных в базах данных Pubmed и РИНЦ. Найдено 399 статей, из которых 62 были включены в данный обзор.

Результаты

Результаты. Белок р53 регулирует целый класс микроРНК – высококонсервативных малых молекул РНК, которые влияют на экспрессию генов в основном путем подавления трансляции. МикроРНК играют важную роль во всех клеточных процессах и могут иметь как онкосупрессорные, так и проонкогенные свойства. Нарушения экспрессии активируемых р53 онкосупрессорных микроРНК в различных опухолях могут быть связаны со специфическими эпигенетическими механизмами (метилированием ДНК и деацетилированием гистонов). В обзоре рассмотрены молекулярно-генетические характеристики онкосупрессорных микроРНК, функционирующих при нормальном кроветворении, нарушение экспрессии которых показано при развитии гемобластозов, а именно: miR-34a, miR-34b/с, miR-145, miR-143 и miR-203. Известно, что транскрипция генов этих микроРНК осуществляется и регулируется с собственных промоторов. Приведены последние опубликованные результаты исследований по диагностическому, прогностическому и клиническому значению метилирования генов рассматриваемых микроРНК при злокачественных новообразованиях системы крови. Согласно данным литературных источников, частыми общими мишенями для микроРНК miR-34a, miR-34b/с, miR-145, miR-143 и miR-203 являются м-РНК ряда проонокогенов, а именно: транскрипционного фактора C-MYC, позитивных регуляторов клеточного цикла в контрольной точке перехода G1/S фаз CDK4, CDK6 и CYCLIN-D1, антиапоптотических белков MDM2, MDM4, ВCL2 и MCL1, а также ДНК-метилтрансфераз DNMT3A и DNMT3B и других молекул. Описано наличие положительных обратных связей между р53 и активируемыми им микроРНК, а также отрицательных обратных связей между р53-респонзивными микроРНК и c-MYC и ДНК-метилтрансферазами.

Заключение

Заключение. Данные, представленные в обзоре, уточняют современные представления о работе регуляторной сети белка р53 и активируемых им микроРНК, а также подчеркивают функциональную ассоциацию р53-респонзивных микроРНК.

The purpose of the study was to present up-to-date data on the frequency and significance of a number of p53-responsive oncosuppressive micrornas genes methylation in malignant neoplasms of the blood system.

Material and methods

Material and methods. The search for available literary sources published in the Pubmed and RISC databases was carried out. A total of 399 articles were found, of which 62 were included in this review.

Results

Results. The p53 protein regulates a whole class of microRNAs – highly conserved small RNA molecules that affect gene expression mainly by suppressing translation. МicroRNAs play an important role in all cellular processes and can have both oncosuppressive and pro-oncogenic properties. Impaired expression of p53-activated oncosuppressive micrornas in various tumors may be associated with specific epigenetic mechanisms (DNA methylation and histone deacetylation). The review examines the molecular and genetic characteristics of oncosuppressive micrornas functioning in normal hematopoiesis, the violation of expression of which is shown in the development of hemoblastoses, namely: miR-34a, miR-34b/c, miR-145, miR-143 and miR-203. It is known that the transcription of the genes of these microRNAs is carried out and regulated from their own promoters. The latest published research results on the diagnostic, prognostic and clinical significance of gene methylation of the microRNAs under consideration in malignant neoplasms of the blood system are presented. According to literature data, common targets for mir-34a, mir-34b/c, mir-145, mir-143 and miR-203 microRNAs are mRNAs of a number of pro-oncogenes, namely: transcription factor C-MYC, positive cell cycle regulators at the G1/S transition point of CDK4, CDK6 and CYCLIN-D1 phases, anti-apoptotic proteins MDM2, MDM4, BCL2 and MCL1, as well as DNMT3A and DNMT3B methyltransferases and other molecules. In this regard, it should be noted that there are positive feedbacks between p53 and microRNAs activated by it, as well as negative feedbacks between p53-responsive micrornas and C-MYC and DNA methyltransferases.

Conclusion

Conclusion. Thus, the data presented in the review clarify the current understanding of the work of the regulatory network of the p53 protein and the micrornas activated by it, and also emphasize the functional association of p53-responsive microRNAs.

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