2658-6533Научные результаты биомедицинских исследований2658-653310.18413/2658-6533-2024-10-1-0-13332Генетика<strong>Ретроэлементы как мишени таргетной терапии опухолей (обзор)</strong><strong>Retroelements in targeted antitumor therapy (review)</strong>МустафинРустам НаилевичMustafinRustam N.ruji79@mail.ruХуснутдиноваЭльза КамилевнаKhusnutdinovaElza K.elzakh@mail.ru202410100

Актуальность:&nbsp;В большинстве злокачественных опухолей определяется патологическая активация ретротранспозонов, которые вызывают геномную нестабильность вследствие воздействия на супрессоры опухолей и онкогены. Это отражается на профилях экспрессии определенных длинных некодирующих РНК и микроРНК в тканях специфических опухолей, поскольку ретроэлементы являются ключевыми источниками возникновения некодирующих РНК. Так как ретроэлементы служат драйверами инициации и прогрессирования канцерогенеза, перспективно применение препаратов, направленных на регуляцию их экспрессии. Цель исследования:&nbsp;Определить имеющиеся методы таргетного воздействия на ретроэлементы в противоопухолевой терапии, оценить пути их дальнейшего совершенствования для эффективного воздействия на злокачественные новообразования. Материалы и методы:&nbsp;Использованы базы данных Scopus, WoS, PubMed для анализа роли ретроэлементов в развитии опухолей, методов воздействия на них при лечении новообразований. Результаты:&nbsp;Эффективными в сайленсинге ретротранспозонов оказались ингибиторы обратной транскриптазы. Воздействия на модификаторы гистонов может приводить к ослаблению противоопухолевого иммунного ответа, поэтому для данного подхода необходимы РНК-гиды, направляющие формирование гетерохроматина в области расположения строго специфических ретроэлементов. Перспективным направлением является метод вирусной мимикрии, направленный на активацию интерферонового и Т-клеточного ответа на искусственным путем активированные эндогенные ретровирусы. Для этого используют ингибиторы метилтрансфераз гистонов, ДНК метилтрансфераз, деацетилаз гистонов. Наиболее эффективна их комбинация, особенно в сочетании с блокаторами контрольной точки PD-1. Расположение ретроэлементов в интронах генов стало основой для разработки сплайсосомной таргетной терапии, также инициирующей противоопухолевый иммунный ответ на двуцепочечные РНК транскрипты. Сделано предположение о возможности применения антисмысловых олигонуклеотидов, нацеленных на ретроэлементы, в противоопухолевой терапии. Такой подход применяется для лечения возрастной дегенерации желтого пятна, мышечной дистрофии Фукуямы, бокового амиотрофического склероза. В противоопухолевой терапии применяют антисмысловые олигонуклеотиды, направленные на микроРНК, протоонкогены и онкосупрессоры, тесно взаимосвязанные с ретроэлементами, которые могут стать перспективными мишенями для данных молекул. Заключение:&nbsp;В терапии опухолей возможно использование двух диаметрально противоположных стратегий воздействия на ретроэлементы: ингибирование и активация. Наиболее перспективный путь &ndash; комбинация данных способов со специфическим сайленсингом ретротранспозонов с помощью гидов (комплементарных РНК) и стимуляцией экспрессии не участвующих в канцерогенезе, но активирующих иммунный ответ элементов.

Background:&nbsp;Pathological expression of retroelements is determined in most malignant tumors, which reflects the pathogenesis of tumors, since activated retrotransposons cause genomic instability due to a cascade of mutual regulatory influence events between transposons, tumor suppressors and oncogenes. These relationships are reflected in the expression profiles of certain long non-coding RNAs and miRNAs in specific tumor tissues, since retroelements are key sources of non-coding RNAs. Since retroelements serve as drivers for the initiation and progression of carcinogenesis, it is promising to use drugs aimed at inhibiting their expression. The aim of the study:&nbsp;To determine the available methods of influencing retroelements in antitumor therapy, to evaluate the ways of their further improvement for the effective treatment of malignant neoplasms. Materials and methods:&nbsp;The databases Scopus, WoS, PubMed were used to analyze the role of retroelements in the development of tumors, methods of influencing them in the treatment of neoplasms. Results:&nbsp;Reverse transcriptase inhibitors have proven to be effective. Silencing of retrotransposons by acting on histone modifiers can lead to a weakening of the antitumor immune response; therefore, this approach requires RNA guides that direct the formation of heterochromatin in the area where strictly specific retroelements are located. A promising method is viral mimicry aimed at activating the interferon and T-cell response to artificially activated endogenous retroviruses. For this purpose, inhibitors of histone methyltransferases, DNA methyltransferases, and histone deacetylases are used. Their joint use is most effective, especially with PD-1 checkpoint blockers. The arrangement of retroelements in gene introns has become the basis for the development of spliceosomal targeted therapy, which also initiates an antitumor immune response to double-stranded RNA transcripts. We suggest the possibility of using antisense oligonucleotides targeting retroelements in anticancer therapy. Such approach is used to treat age-related macular degeneration, Fukuyama muscular dystrophy, amyotrophic lateral sclerosis. Antisense oligonucleotides targeting microRNAs, proto-oncogenes, and oncosuppressors are used in anticancer therapy and are closely related to retroelements, which could become promising targets for antisense oligonucleotides. Conclusion:&nbsp;In antitumor therapy, it is possible to use two diametrically opposed strategies for influencing retroelements: inhibition and activation. The most promising way is a combination of these methods with specific silencing of retrotransposons using guides (complementary RNAs) and stimulation of the expression of elements not involved in carcinogenesis, but activating the immune response.

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