Genes & CellsGenes & CellsГены и КлеткиGenes and Cells2313-18292500-2562Human Stem Cells Institute12194910.23868/202110002ArticlesСтатьиReview ArticleTransposon hypothesis of carcinogenesisТранспозонная гипотеза канцерогенезаMustafinR. NМустафинР. Нruji79@mail.ruBashkir State Medical UniversityБашкирский государственный медицинский университет15092021163VOL 16, NO3 (2021)ТОМ 16, №3 (2021)81516012023Copyright ©; 2021, Eco-VectorCopyright ©; 2021, Эко-Вектор2021Eco-VectorЭко-Векторhttps://genescells.ru/2313-1829/article/view/121949

The hypothesis is presented according to which the key drivers of carcinogenesis are transposons causing genomic instability, activation of oncogenes and inactivation of oncosuppressor genes. Expression of retroelements is under the negative regulatory control of proteins p53, RB1, VHL, BRCA1, ATM. It is assumed that most oncosuppressors have this property, since their genes are characterized by the presence in their composition of mobile elements (causing recombinations upon their activation) and hot spots of insertional mutagenesis. Accordingly, suppression of the expression of transposons as an adaptive process is necessary to ensure the stability of these genes. Therefore, the development of neoplasms in hereditary tumor syndromes may be due to pathological activation of transposons, which cause mutation of the second allele and other oncosuppressor genes due to congenital deficiency of oncosuppressor. Identical mechanisms are likely for sporadic carcinogenesis, when an activated transposon moves to new loci, causes complex genomic rearrangements specific to neoplasms, and inactivates oncosuppressors. Since the sequences of the transposable elements serve as alternative promoters for many genes, their activation causes enhanced expression of oncogenes in carcinogenesis. The transposons located in introns facilitate the transcription of chimeric molecules that have a pronounced oncogenic activity. In addition, mobile elements are sources of oncogenic microRNAs and long noncoding RNAs. The same microRNAs affect both neoplasms and aging, which confirms the hypothesis put forward, since dysregulation of mobile elements occurs with age, and aging is associated with an increased risk of cancer developing.

Представлена гипотеза, согласно которой ключевыми драйверами канцерогенеза являются транспозоны, вызывающие геномную нестабильность, экспрессию онкогенов и инактивацию онкосупрессорных генов. Экспрессия ретроэлементов находится под негативным регуляторным контролем белков р53, RB1, VHL, BRCA1, ATM. Предполагают, что большинство онкосупрессоров способны вызывать сайленсинг транспозонов, так как в их генах содержатся мобильные элементы, вызывающие рекомбинацию при их активации, и горячие точки инсерционного мутагенеза. Подавление экспрессии транспозонов онкосупрессорами в качестве адаптивного процесса к нормальному развитию организма, направленное на устранение возможности геномной нестабильности, необходимо для обеспечения стабильности этих генов. Причиной развития новообразований при наследственных опухолевых синдромах может стать обусловленная врожденным дефицитом онкосупрессора патологическая активация транспозонов, которые вызывают мутации второго аллеля и других онкосупрессорных генов. таким образом, при развитии опухолей формируется «порочный круг»: мобильные элементы инактивируют онкосупрессоры, необходимые для подавления экспрессии транспозонов, что вызывает активацию большего количества мобильных элементов и прогрессирующую геномную нестабильность, а вновь активированные транспозоны вызывают мутации в других онкосупрессорных генах. Идентичные механизмы вероятны для спорадического канцерогенеза: активированный под влиянием стрессовых факторов и соматических мутаций транспозон перемещается в новые локусы, вызывает характерные для неоплазм комплексные геномные перестройки, инактивирует онкосупрессоры, содержащие горячие точки инсерционного мутагенеза, и активирует онкогены, поскольку их регуляторные области и интроны содержат в своем составе транспозоны. расположенные в интронах транспозоны способствуют транскрипции химерных молекул, которые обладают выраженной онкогенной активностью. Кроме того, мобильные элементы являются источниками онкогенных микрорНК и длинных некодирующих рНК. одни и те же микрорНК влияют на развитие неоплазм и старение организма, что подтверждает гипотезу о роли транспозонов в канцерогенезе, так как с возрастом происходит активация транспозонов, а старение ассоциировано с высоким риском развития злокачественных опухолей.

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