Head and Neck TumorsHead and Neck TumorsОпухоли головы и шеи2222-14682411-4634Publishing House ABV Press88610.17650/2222-1468-2023-13-2-26-34DIAGNOSIS AND TREATMENT OF HEAD AND NECK TUMORSДИАГНОСТИКА И ЛЕЧЕНИЕ ОПУХОЛЕЙ ГОЛОВЫ И ШЕИProspects of epigenetic therapy of head and neck squamous cell carcinomaПерспективы эпигенетической терапии плоскоклеточного рака головы и шеиhttps://orcid.org/0000-0002-4091-382XMustafinR. N.МустафинР. Н.
Russian Federation

Rustam Nailevich Mustafin

3 Lenin St., Ufa 450008

Рустам Наилевич Мустафин

450008 Уфа, ул. Ленина, 3

ruji79@mail.ruBashkir State Medical University, Ministry of Health of RussiaФГБОУ ВО «Башкирский государственный медицинский университет» Минздрава России1309202313226341209202312092023Copyright ©; 2023, Mustafin R.N.Copyright ©; 2023, Мустафин Р.Н.2023Mustafin R.N.Мустафин Р.Н.https://creativecommons.org/licenses/by/4.0https://ogsh.abvpress.ru/jour/article/view/886

Introduction. Head and neck squamous cell carcinoma is the 6th most common malignant tumor. It is characterized by immune response evasion and drug resistance. To stimulate antitumor immune response, antibodies against such cell cycle checkpoints as programmed cell death 1 (pD-1) and programmed death-ligand 1 (pD-L1) are used. However, effectiveness of monotherapy with these checkpoint inhibitors turned out to be low, and combinations with other antitumor drugs have high risk of adverse events.

Aim. To determine the most practical ways to influence epigenetic factors in treatment of head and neck squamous cell carcinoma.

Materials and methods. Scientific literature published between 2011 and 2022 and indexed in the eLIBRARY, Scopus, woS, NCBI databases (398 articles, of which 76 were used) was analyzed.

Results. prospects of development of epigenetic stimulation of expression of retroelements located in tumor genomes through inhibition of DNA methyltransferases, deacetylases and histone methyltransferases were considered. when retroelements are activated, their transcripts form double-stranded RNA stimulating T killers and interferon response (virus mimicry). for DNA methyltransferase inhibitors, restoration of tumor suppressor genes which are hypermethylated in squamous cell carcinoma is also observed. However, retroelement activation is a driver mechanism of carcinogenesis, and their nonspecific expression can lead to tumor progression and formation of secondary tumors. Therefore, in the virus mimicry method it is practical to use as targets microRNA complementary to retroelements which recruit epigenetic factors to their loci (RNA-directed DNA methylation), as well as antisense oligonucleotides against oncogenic microRNA associated with retroelements. These approaches allow to inhibit retroelements participating in carcinogenesis. Nonspecific method of retrotransposon activity suppression is being developed in antitumor therapy, but data show successful application of only reverse transcriptase inhibitors preventing insertions and progression of genomic instability. we have performed analysis of scientific literature on transposable elements-derived microRNA associated with head  and  neck  squamous  cell  carcinoma.  As  a  result,  31  microRNAs  were  identified,  derived  from:  LINE:  miR-1249, -151a, -211, -2355, -28, -31, -3144, -374a, -374b, -421, -450b, -511, -576, -577, -582, -708, -769, -887, -95; HERv: miR-1269a,  -1911,  -3200,  -495;  non-autonomous  SINE:  miR-335,  -342,  -378a,  -3934,  -487b;  DNA  transposons:  miR-224, -584, -652. These microRNAs can serve as the basis for epigenetic therapy of head and neck squamous cell carcinoma.

Введение. плоскоклеточный рак головы и шеи занимает 6-е место по распространенности среди всех злокачественных новообразований и характеризуется уклонением клеток от иммунного ответа и фармакорезистентностью. Для стимуляции противоопухолевого иммунного ответа используются антитела против таких контрольных точек, как рецептор программируемой клеточной гибели 1 (programmed cell death 1, pD-1) и его лиганд (programmed death-ligand 1, pD-L1), эффективность монотерапии которыми оказалась низкой, а в комбинации с другими противоопухолевыми препаратами определен высокий риск развития побочных эффектов.

Цель исследования – определить наиболее целесообразные пути воздействия на эпигенетические факторы в лечении плоскоклеточного рака головы и шеи.

Материалы и методы. проанализирована научная литература за 2011–2022 гг., опубликованная на сайтах eLIBRARY, Scopus, woS, NCBI (398 статей, из которых использованы 76).

Результаты. Определена перспективность разработки эпигенетической стимуляции экспрессии расположенных в геномах опухолей ретроэлементов за счет ингибирования ДНК-метилтрансфераз, деацетилаз и метилтрансфераз гистонов. при активации ретроэлементов их транскрипты образуют двуцепочечные РНК, стимулирующие т-киллеры и интерфероновый ответ против опухоли (вирусная мимикрия). Для ингибиторов ДНК-метилтрансфераз отмечено также восстановление экспрессии генов-супрессоров опухолей, которые гиперметилируются при плоскоклеточном раке. Однако активация ретроэлементов является драйверным механизмом канцерогенеза, и их неспецифическая экспрессия может привести к прогрессированию опухолевого процесса или образованию вторичных опухолей. поэтому в методе вирусной мимикрии в качестве мишеней для таргетного воздействия перспективно использование комплементарных ретроэлементам микроРНК, рекрутирующих в их локусы эпигенетические факторы (феномен РНК-направленного ДНК-метилирования), а также антисмысловых олигонуклеотидов против ассоциированных с ретроэлементами онкогенных микроРНК. такими путями можно ингибировать ретроэлементы, участвующие в канцерогенезе. Неспецифический метод подавления активности ретротранспозонов разрабатывается в противоопухолевой терапии, однако получены данные об успешном применении лишь ингибиторов обратной транскриптазы, предотвращающих инсерции и прогрессирование геномной нестабильности. Мы провели анализ научной литературы о происходящих от транспозонов микроРНК, ассоциированных с плоскоклеточным раком головы и шеи. В результате найдены 31 микроРНК, которые возникли: от LINE – miR-1249, -151a, -211, -2355, -28, -31, -3144, -374a, -374b, -421, -450b, -511, -576, -577, -582, -708, -769, -887, -95; от HERv– miR-1269a, -1911, -3200, -495; от неавтономных SINE – miR-335, -342, -378a, -3934, -487b; от ДНК-транспозонов: miR-224, -584, -652. Данные микроРНК могут стать основой для эпигенетической терапии плоскоклеточного рака головы и шеи.

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