Влияние ретроэлементов на онкогены и онкосупрессоры в канцерогенезе

Мустафин Р.Н. Влияние ретроэлементов на онкогены и онкосупрессоры в канцерогенезе. Современная Онкология. 2021;23(4):666–673. DOI: 10.26442/18151434.2021.4.201199

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Mustafin RN. Influence of retroelements on oncogenes and tumor suppressors in carcinogenesis: A review. Journal of Modern Oncology. 2021;23(4):666–673. DOI: 10.26442/18151434.2021.4.201199

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Аннотация

Анализ данных научной литературы показал, что ретротранспозоны при активации участвуют в канцерогенезе различными путями. Во-первых, они могут кодировать собственно онкогены. Примером является белок Np9, синтезируемый эндогенным ретровирусом HERV-K. Во-вторых, ретроэлементы (РЭ) используются в качестве альтернативных промоторов протоонкогенов. Соответственно, их активация способствует усиленной экспрессии онкогенов. Примерами являются гены CSF1R, IRF5, MET, RAB3IP, CHRM3. В-третьих, транспозоны располагаются в интронах некоторых генов и при активации образуют химерные транскрипты, такие как LTR2-FABP7, LTR-ALK, LTR-ERBB4, LINE1-MET, обладающие выраженной онкогенной активностью. В-четвертых, РЭ перемещаются в гены онкосупрессоров и инактивируют их, что связано с наличием в них горячих точек инсерционного мутагенеза. Данная особенность доказана в отношении известных онкосупрессорных генов (ОСГ) APC, NF1, MSH2, PTEN, RB1, TSC2, STK11, VHL. В результате стимулируются рост опухолей и выживаемость их клеток. Важно отметить, что белковые продукты таких ОСГ, как ТР53, RB1, VHL, BRCA1, ATM, обладают способностью ингибировать активность РЭ. Соответственно, при инактивации даже одного ОСГ может срабатывать своеобразный «порочный круг», когда ослабляется контроль экспрессии РЭ. Последние в свою очередь инактивируют другие онкосупрессоры, содержащие горячие точки инсерционного мутагенеза. Этот процесс стимулирует новые пути канцерогенеза и выработку онкогенов, связанных с транспозонами. Таким образом, можно по-новому объяснить механизмы образования опухолей при наследственном опухолевом синдроме, поскольку ослабления функции онкосупрессора при герминативной гетерозиготной мутации может быть достаточно для запуска «порочного круга» с участием РЭ, онкогенов и других онкосупрессоров. Сходные механизмы вероятны для спорадического канцерогенеза. Однако инициирующим событием может стать непосредственная активация транспозонов под действием стрессоров, химических и физических канцерогенов. Помимо описанных событий активация РЭ вызывает геномную нестабильность, способствующую комплексным геномным перестройкам, часто наблюдаемым в злокачественных опухолях. Важную роль в эволюции опухолей играют также микроРНК и длинные некодирующие РНК, источниками которых являются РЭ. Их изучение перспективно для разработки таргетной терапии неоплазм.

Ключевые слова: вирусы, длинные некодирующие РНК, канцерогенез, микроРНК, онкогены, онкосупрессоры, ретроэлементы

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Analysis of scientific literature data has revealed several ways in which retrotransposons, when activated, are involved in carcinogenesis. First, retroelements can encode oncogenic proteins. For example, the Np9 protein is translated from HERV-K endogenous retrovirus transcript. Second, retroelements are used as alternative promoters of protooncogenes. Accordingly, their activation contributes to the enhanced expression of oncogenes (e.g. CSF1R, IRF5, MET, RAB3IP, CHRM3). Third, retroelements are located in the introns of some genes, and upon their activation, they form chimeric transcripts, such as LTR2-FABP7, LTR‑ALK, LTR-ERBB4, LINE1-MET, which have pronounced oncogenic activity. Fourth, retroelements are transposed into tumor suppressor genes (e.g. APC, NF1, MSH2, PTEN, RB1, TSC2, STK11, VHL) and inactivate them, which is associated with the presence of hot spots of insertional mutagenesis in them. As a result, the growth of tumors and the survival of their cells are stimulated. It is important to note that protein products of tumor suppressor genes, such as TP53, RB1, VHL, BRCA1, ATM, are characterized by the ability to inhibit the activity of retroelements. Accordingly, when even one oncosuppressive gene is inactivated, a kind of "vicious circle" can be triggered when the control of expression of retroelements is weakened. The latter, in turn, inactivate other tumor suppressors containing hot spots of insertional mutagenesis. This stimulates new pathways of carcinogenesis and the production of oncogenes associated with transposons. Thus, it is possible to explain in a new way the mechanisms of tumor formation in hereditary tumor syndromes. This is due to the fact that the weakening of the function of an oncosuppressor in a germinal heterozygous mutation may be sufficient to trigger a “vicious circle” involving retroelements, oncogenes and other oncosuppressors. Similar mechanisms are likely for sporadic malignant tumors. However, the initiating event in them can be the direct activation of transposons under the influence of stressors, chemical and physical carcinogens. In addition to the events described, activation of retroelements causes genomic instability, which contributes to complex genomic rearrangements often observed in malignant tumors. MicroRNAs and long noncoding RNAs, the sources of which are retroelements, also play an important role in the evolution of tumors. Their study is promising for the development of targeted therapy for neoplasms.

Keywords: viruses, long noncoding RNAs, carcinogenesis, microRNAs, oncogenes, oncosuppressors, retroelements

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5. Babaian A, Romanish MT, Gagnier L, et al. Onco-exaptation of an endogenous retroviral LTR drives IRF5 expression in Hodgkin lymphoma. Oncogene. 2016;35:2542-6.
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14. Mita P, Sun X, Fenyo D, et al. BRCA1 and S phase DNA repair pathways restrict LINE-1 retrptransposition in human cells. Nat Struct Mol Biol. 2020;27:179-91.
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Авторы

Р.Н. Мустафин*

ФГБОУ ВО «Башкирский государственный медицинский университет» Минздрава России, Уфа, Россия
*e-semina@yandex.ru

________________________________________________

Rustam N. Mustafin*

Bashkir State Medical University, Ufa, Russia
*e-semina@yandex.ru

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