EPIGENETICS OF CARCINOGENESIS

Currently, the key mechanisms of carcinogenesis are epigenetic events. Epigenetic factors include DNA methylation, histone modifications, microRNA expression and higher chromatin organization. Non-coding RNAs include microRNAs, small interfering RNAs or siRNAs, piRNAs, long noncoding RNAs or lncRNAs. According to recent data, most of these RNAs are directly formed from mobile genetic elements or have a transposon origin. Non-coding RNAs specifically affect the methylation of the genome and the modification of histones in ontogenesis. This is facilitated by evolutionarily programmed features of activation of transposons, since non-coding RNAs are formed from transposons. Thus, the material basis of epigenetic heredity are the transposons. Stress and aging increase the likelihood of developing cancer. This can be explained by an increase in the number of abnormal activation of mobile genetic elements that are sensitive to stress and hormones. Abnormal activation of transposons in cells leads to genomic instability-most such cells undergo apoptosis. However, in some cases, progressive genomic instability leads to damage to oncospressor genes and oncogenes activation - as a result of apoptosis does not occur, and cells acquire the ability of uncontrolled proliferation with the accumulation of a variety of mutations due to the progressive genomic instability caused by the mobilization of transposons. In each type of malignant tumors, specific cascade mechanisms of activation of mobile genetic elements with the participation of non-coding RNA are triggered. The study of epigenetic mechanisms of development of each type of cancer will enable to develop effective methods for early molecular genetic diagnosis of cancer, as well as targeted therapy at different stages of carcinogenesis.

: genomic instability, long noncoding RNA (lncRNA), methylation, microRNA, non-allelic homologous recombination, non-coding RNA, retrotransposition, transposons

1. Майборода АА. Гены и белки онкогенеза. Сибирский медицинский журнал. 2013;(2):132-138. [Mayboroda AA. Genes and proteins of oncogenesis. Sibirskiy meditsinskiy zhurnal = Siberian Medical Journal. 2013;(2):132-138. (in Russ.)].

2. Имянитов ЕН. Общие представления о таргетной терапии. Практическая онкология. 2010;11(3):123-130. [Imyanitov EN. General ideas about targeted therapy. Prakticheskaya onkologiya = Practical oncology. 2010;11(3):123-130. (in Russ.)].

3. Herceg Z, Lambert M, van Veldhoven K, Demetriou C, Vineis P, Smith MT, et al. Towards incorporating epigenetic mechanisms into carcinogen identification and evaluation. Carcinogenesis. 2013;34(9):1955-67. DOI: 10.1093/carcin/bgt212.

4. Samantarrai D, Dash S, Chhetri B, Mallick B. Genomic and epigenomic cross-talks in the regulatory landscape of miRNAs in breast cancer. Mol Cancer Res. 2013;11(4):315-28. DOI: 10.1158/1541-7786. MCR-12-0649.

5. Giordano S, Columbano A. MicroRNA: new tools for diagnosis, prognosis, and therapy in hepatocellular carcinoma? Hepatology. 2013;57(2):840-847. DOI: 10.1002/hep.26095.

6. Цуканов АС, Шубин ВП, Поспехова НИ, Сачков ИЮ, Кашников ВН, Шелыгин ЮА. Наследственные раки желудочно-кишечного тракта. Практическая онкология. 2014;15(3): 126-133. [Tsukanov AS, Shubin VP, Pospekhova NI, Sachkov IYu, Kashnikov VN, Shelygin YuA. Hereditary cancers of the gastrointestinal tract. Prakticheskaya onkologiya = Practical oncology. 2014;15(3):126-133. (in Russ.)].

7. Заридзе ДГ. Канцерогенез. М.;2004. [Zaridze DG. Carcinogenesis. M.;2004. (in Russ.)].

8. Moyano M, Stefani G. PiRNA involvement in genome stability and human cancer. J Hematol Oncol. 2015;8:38-47. DOI: 10.1186/s13045-015-0133-5.

9. Rodic N, Burns KH. Long interspersed element-1 (LINE-1): passenger or driver in human neoplasms? PLOS Genetics. 2013;9(3):e1003402. DOI: 10.1371/ journal.pgen.1003402.

10. Chen L, Dahlstrom JE, Lee S, Rangasamy D. Naturally occurring endo-siRNA silences LINE1 retrotransposons in human cells through DNA methylation. Epigenetics. 2012;7(7):758-77. DOI: 10.4161/epi.20706.

11. Сидельников ГД, Валихов АФ. О роли эндогенных ретровирусов в биологии опухолевого роста. Вопросы онкологии. 2016;62(6):758-766. [Sidel’nikov GD, Valikhov AF. About the role of endogenous retroviruses in the biology of tumor growth. Voprosy onkologii = Problems in oncology. 2016;62(6):758766. (in Russ.)].

12. Morales-Hernandez A, Gonzalez-Rico FJ, Roman AC, Rico-Leo E, Alvarez-Barrientos A, Sanchez L, et al. Alu retrotransposons promote differentiation of human carcinoma cells through the aryl hydrocarbon receptor. Nucleic Acids Res. 2016;44(10):4665-4683. DOI: 10.1093/nar/gkw095.

13. Sturm A, Ivics Z, Vellai T. The mechanism of ageing: primary role of transposable elements in genome disintegration. Cell Mol Life Sci. 2015;72(10):1839-47. DOI: 10.1007/s00018-015-1896-0.

14. Gim J, Ha H, Ahn K, Kim DS, Kim HS. Genomewide identification and classification of microRNAs derived from repetitive elements. Genomic Inform. 2014;12(4):261-267. DOI: 10.5808/GI.2014.12.4.261.

15. Киселев ОИ. Эндогенные ретровирусы: структура и функция в геноме человека. Вопросы вирусологии. 2013;(S1):102-115. [Kiselev OI. Endogenous retroviruses: structure and function in the human genome. Voprosy virusologii = Problems of virology. 2013;(S1):102-115. (in Russ.)].

16. Ohms S, Rangasamy D. Silencing of LINE1 retrotransposons contributes to variation in small noncoding RNA expression in human cancer cells. Oncotarget. 2014;5(12):4103-17. DOI: 10.18632/ oncotarget.1822.

17. Spengler RM, Oakley CK, Davidson BL. Functional microRNAs and target sites are created by lineage-specific transposition. Hum Mol Genet. 2014;23(7):1783-93. DOI: 10.1093/hmg/ddt569.

18. Roberts JT, Cooper EA, Favreau CJ, Howell JS, Lane LG, Mills JE, et al. Continuing analysis of microRNA origins: Formation from transposable element insertions and noncoding RNA mutations. Mob Genet Elements. 2013;1(6):е27755. DOI: 10.4161/mge.27755.

19. Borchert GM, Holton NW, Williams JD, Hernan WL, Bishop IP, Dembosky JA, et al. Comprehensive analysis of microRNA genomic loci identifies pervasive repetitive-element origins. Mob Genet Elements. 2011;1(1):8-17. DOI: 10.4161/mge.1.1.15766.

20. Johnson R, Guigo R. The RIDL hypothesis: transposable elements as functional domains of long noncoding RNAs. RNA. 2014;20(7):959-976. DOI: 10.1261/rna.044560.114.

21. Васильева ЛА, Антоненко ОВ, Выхристюк ОВ, Захаров ИК. Селекция изменяет паттерн мобильных генетических элементов в геноме Drosophila Melanogaster. Вестник ВОГиС. 2008;12(3):412-425. [Vasil’eva LA, Antonenko OV, Vykhristyuk OV, Zakharov IK. Selection changes the pattern of mobile genetic elements in genome of Drosophila Melanogaster. Vestnik VOGiS = VOIPS Bulletin. 2008;12(3):412-425. (in Russ.)].

22. Pavlicev M, Hiratsuka K, Swaqqart KA, Dunn C, Muglia L. Detecting endogenous retrovirus-driven tissue-specific gene transcription. Genome Biol Evol. 2015;7(4):1082-97. DOI: 10.1093/gbe/evv049.

23. Kitkumthorn N, Mutirangura A. Long interspersed nuclear element-1 hypomethylation in cancer: biology and clinical applications. Clin Epigenet. 2011;2:315-330. DOI:10.1007/s13148-011-0032-8.

24. Szpakowski S, Sun X, Lage JM, Dyer A, Rubinstein J, Kowalski D, et al. Loss of epigenetic silencing in tumors preferentially affects primatespecific retroelements. Gene. 2009;448(2):151-167. DOI: 10.1016/j.gene.2009.08.006.

25. Wylie A, Jones AE, D’Brot A, Lu WJ, Kurtz P, Moran JV, et al. P53 genes function to restrain mobile elements. Genes Dev. 2016;30(1):64-77. DOI: 10.1101/ gad.266098.115.

26. Li P, Chen S, Xia T, Jiang XM, Shao YF, Xiao BX. et al. Non-coding RNAs and gastric cancer. World J Gastroenterol. 2014;20(18):5411-19. DOI: 10.3748/wjg. v20.i18.5411.

27. Han C, Shen JK, Hornicek FJ, Kan Q, Duan Z. Regulation of microRNA-1 (miR-1) expression in human cancer. Biochim Biophys Acta. 2017;1860(2):227-232. DOI: 10.1016/j.bbagrm.2016.12.004.

28. Patutina OA, Bichenkova EV, Miroshnichenko SK, Mironova NL, Trivoluzzi LT, Burusco KK, et al. MiRNases: Novel peptide-oligonucleotide bioconjugates that silence miR-21 in lymphosarcoma cells. Biomaterials. 2017;122:163-178. DOI: 10.1016/j. biomaterials.2017.01.018.

29. Sakabe T, Azumi J, Umekita Y, Toriguchi K, Hatano E, Hirooka Y, et al. Prognostic relevance of miR137 in patients with hepatocellular carcinoma. Liver Int. 2017;37(2):271-279. DOI: 10.1111/liv.13213.

30. Fukagawa S, Miyata K, Yotsumoto F, Kiyoshima C, Nam SO, Anan H. et al. MiR-135a-3p a promising biomarker and nuckeic acid therapeutic agent for ovarian cancer. Cancer Sci. 2017;108(5):886-896. DOI: 10.1111/cas.13210.

31. Zhou W, Wang S, Ying Y, Zhou R, Mao P. MiR196b/miR-1290 participate in the antitumor effect of resveratrol via regulation of IGFBP3 expression in acute lymphoblastic leukemia. Oncol Rep. 2017;37(2):10751083. DOI: 10.3892/or.2016.5321.

32. Hodzic J, Sie D, Vermeulen A, van Beusechem VW. Functional screening identifies human miRNAs that modulate adenovirus propagation in prostate cancer cells. Hum Gene Ther. 2017 Jan: 23. DOI: 10.1089/hum.2016.143.