Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press60310.17650/2313-805X-2023-10-4-21-30REVIEWОБЗОРНАЯ СТАТЬЯRelationship of transposable elements with long non-coding RNAs and peptides in carcinogenesisВзаимосвязь транспозонов с длинными некодирующими РНК и пептидами в канцерогенезеhttps://orcid.org/0000-0002-4091-382XMustafinR. N.МустафинР. Н.
Russian Federation

Rustam N. Mustafin.

3 Lenin St., Ufa 450008

Мустафин Рустам Наилевич.

450008 Уфа, ул. Ленина, 3

ruji79@mail.ruBashkir State Medical University, Ministry of Health of RussiaФГБОУ ВО «Башкирский государственный медицинский университет» Минздрава России1512202310421301202202214122023Copyright ©; 2023, Mustafin R.N.Copyright ©; 2023, Мустафин Р.Н.2023Mustafin R.N.Мустафин Р.Н.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/603

It has been proven that 98 % of the human genome is transcribed. The main part of resulting molecules after their processing function as various RNA molecules, among which the best known are long noncoding RNA (lncRNA)  and microRNA. There are 126,000 lncRNA genes in humans that regulate transcription, translation, histone modifications, heterochromatin formation, splicing, microRNA expression and formation, and matrix RNA (mRNA)  post-transcriptional modifications. An important property of lncRNAs is their mutual and self-regulation by peptides formed during their translation, which also affect the expression of protein-coding genes. This property may be due to origin of lncRNAs from transposable elements and is a conservative evolutionary characteristic of lncRNA, as one of properties in formation of new genes for variability and adaptation.  The role of lncRNAs originating from retroelements and microRNAs formed during their processing in the specific regulation of genes involved in carcinogenesis has been proven. The peptides formed during lncRNA translation can be used as universal tools for targeted therapy of malignant neoplasms. Analysis of the scientific literature  made it possible to describe 21 lncRNAs that  are translated  to form peptides involved in specific tumors pathogenesis. Since the ability of lncRNA to self-regulate by products of its own translation, which is characteristic of all lncRNAs, is also a property of transposable elements, it is promising to study transposons and their relationship with lncRNAs for designing new therapeutic models.

Доказано, что 98 % генома человека транскрибируется. Основная часть образующихся при этом молекул после их процессинга функционирует в качестве различных молекул РНК, среди которых наиболее известны длинные некодирующие РНК (днРНК) и микроРНК. У человека выявлены 126 тыс. генов днРНК, регулирующих транскрипцию, трансляцию, модификации гистонов, образование гетерохроматина, сплайсинг, экспрессию и формирование микроРНК, а также посттранскрипционные модификации матричной РНК (мРНК). Важным свойством днРНК является взаимо- и саморегуляция образующимися при их трансляции пептидами, которые влияют также на экспрессию белок-кодирующих генов. Данное свойство может быть обусловлено происхождением днРНК от транспозонов и представляет собой консервативную эволюционную характеристику днРНК как одно из свойств при образовании новых генов для изменчивости и адаптации. Доказана роль возникших от ретроэлементов днРНК и образуемых при их процессинге микроРНК в специфической регуляции генов, участвующих в канцерогенезе. Образуемые при трансляции днРНК пептиды могут быть использованы как универсальные инструменты для таргетной терапии злокачественных новообразований. Анализ научной литературы позволил описать 21 днРНК, которая транслируется с образованием пептидов, вовлеченных в патогенез специфических опухолей. поскольку способность днРНК к саморегуляции продуктами собственной трансляции, которая характерна для всех днРНК, является также свойством транспозонов, перспективно исследование мобильных генетических элементов и их взаимосвязи с днРНК для проектирования новых терапевтических моделей.

long non-coding RNAsmalignant neoplasmscarcinogenesismiRNAstransposonsretroelementsдлинные некодирующие РНКзлокачественные новообразованияканцерогенезмикроРНКтранспозоныретроэлементыKour S., Rath P.C. Long noncoding RNAs in aging and age-related diseases. Ageing Res Rev 2016;26:1–21. DOI: 10.1016/j.arr.2015.12.001Fico A., Fiorenzano A., Pascale E. et al. Long non-coding RNA in stem cell pluripotency and lineage commitement: functions and evolutionary conservation. Cell Mol Life Sci 2019;76:1459–71. DOI: 10.1007/s00018-018-3000-zDe Koning A.P., Gu W., Castoe T.A. et al. Repetitive elements may comprise over two-thirds of the human genome. PLoS Genetics 2011;7(12):e1002384. DOI: 10.1371/journal.pgen.1002384Kelley D., Rinn J. Transposable elements reveal a stem cell-specific class of long noncoding RNAs. Genome Biol 2012;13(11):R107. DOI: 10.1186/gb-2012-13-11-r107Gibb E.A., Brown C.J., Lam W.L. The functional role of long non-coding RNA in human carcinomas. Mol Cancer 2011;10:38. DOI: 10.1186/1476-4598-10-38Mustafin R.N., Khusnutdinova E.K. The role of retroelements in the development of hereditary tumor syndromes. Uspekhi molekulyarnoy onkologii = Advances in Molecular Oncology 2021;8(4):42–52. (In Russ.). DOI: 10.17650/2313-805X-2021-8-4-42-52Мустафин Р.Н., Хуснутдинова Э.К. Роль ретроэлементов в развитии наследственных опухолевых синдромов. Успехи молекулярной онкологии 2021;8(4):42–52. DOI: 2313-805X-2021-8-4-42-52Haack D.B., Toor N. Retroelement origins of pre-mRNA splicing. Wiley Interdiscip Rev RNA 2020;11(4):e1589. DOI: 10.1002/wrna.1589Mustafin R.N. Functional dualism of transposon transcripts in the evolution of eukaryotic genomes. Ontogenesis 2018;4S1:3–20. (In Russ.).Мустафин Р.Н. Функциональный дуализм транскриптов транспозонов в эволюции эукариотических геномов. Онтогенез 2018;4S1:3–20.Ye D., Jiang D., Li Y. et al. The role of LINE-1 methylation in predicting survival among colorectal cancer patients: a meta-analysis. Int J Clin Oncol 2017;22(4):749–57. DOI: 10.1007/s10147-017-1106-1Barchitta M., Quattrocchi A., Maugeri A. et al. LINE-1 hypomethylation in blood and tissue samples as an epigenetic marker for cancer risk: a systematic review and meta-analysis. PLoS One 2014;9(10):e109478. DOI: 10.1371/journal.pone.0109478Ye D., Jiang D., Zhang X., Mao Y. Alu methylation and risk of cancer: a meta-analysis. Am J Med Sci 2020;359(5):271–80. DOI: 10.1016/j.amjms.2020.03.002Jang H.S., Shah N.M., Du A.Y. et al. Transposable elements drive widespread expression of oncogenes in human cancer. Nat Genet 2019;51(4):611–7. DOI: 10.1038/s41588-019-0373-3Rodriguez-Martin B., Alvarez E.G., Baez-Ortega A. et al. Pancancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition. Nat Genet 2020;52(3):306–19. DOI: 10.1038/s41588-019-0562-0Steiner M.C., Marston J.L., Iniguez L.P. et al. Locus-specific characterization of human endogenous retrovirus expression in prostate, breast, and colon cancers. Cancer Res 2021;81(13):3449–60. DOI: 10.1158/0008-5472.CAN-20-3975Lu X., Sachs F., Ramsay L. et al. The retrovirus HERVH is a long noncoding RNA required for human embryonic stem cell identity. Nat Struct Mol Biol 2014;21(4):423–5. DOI: 10.1038/nsmb.2799Lu S., Zhang J., Lian X. et al. A hidden human proteome encoded by ‘non-coding’ genes. Nucleic Acids Res 2019;47(15):8111–25. DOI: 10.1093/nar/gkz646Grammatikakis I., Panda A.C., Abdelmohsen K., Gorospe M. Long noncoding RNAs (lncRNAs) and the molecular hallmarks of aging. Aging (Albany NY) 2014;6(12):992–1009. DOI: 10.18632/aging.100710Feschotte C. Transposable elements and the evolution of regulatory networks. Nat Rev Genet 2008;9(5):397–405. DOI: 10.1038/nrg2337Hadjiargyrou M., Delihas N. The intertwining of transposable elements and non-coding RNAs. Int J Mol Sci 2013;14(7):13307–28.Abdelmohsen K., Gorospe M. Noncoding RNA control of cellular senescence. Wiley Interdiscip Rev RNA 2015;6(6):615–29.Jin X., Xu X., Jiang Y. et al. The endogenous retrovirus-derived long noncoding RNA TROJAN promotes triple-negative breast cancer progression via ZMYND8 degradation. Sci Adv 2019;5(3):eaat9820. DOI: 10.1126/sciadv.aat9820Wu Y., Zhao Y., Huan L. et al. An LTR retrotransposon-derived long noncoding RNA lncMER52A promotes hepatocellular carcinoma progression by binding p120-Catenin. Cancer Res 2020;80(5):976–87. DOI: 10.1158/0008-5472.CAN-19-2115Kulski J.K. Long noncoding RNA HCP5, a hybrid HLA class I endogenous retroviral gene: structure, expression, and disease associations. Cells 2019;8(5):480. DOI: 10.3390/cells8050480Deng B., Xu W., Wang Z. et al. An LTR retrotransposon-derived lncRNA interacts with RNF169 to promote homologous recombination. EMBO Rep 2019;20(11):e47650. DOI: 10.15252/embr.201847650Prel A., Dozier C., Combier J.P. et al. Evidence that regulation of Pri-miRNA/miRNA expression is not a general rule of miPEPs function in humans. Int J Mol Sci 2021;22(7):3432. DOI: 10.3390/ijms22073432Testa U., Pelosi E., Castelli G., Labbaye C. miR-146 and miR-155: two key modulators of immune response and tumor development. Noncoding RNA 2017;3(3):22. DOI: 10.3390/ncrna3030022Niu L., Lou F., Sun Y. et al. A micropeptide encoded by lncRNA MIR155HG suppresses autoimmune inflammation via modulating antigen presentation. Sci Adv 2020;6(21):eaaz2059. DOI: 10.1126/sciadv.aaz2059Augoff K., McCue B., Plow E.F., Sossey-Alaoui K. MiR-31 and its host gene lncRNA LOC554202 are regulated by promoter hypermethylation in triple-negative breast cancer. Mol Canc 2012;11:5. DOI: 10.1186/1476-4598-11-5Collette J., Le Bourhis X., Adriaenssens E. Regulation of human breast cancer by the long non-coding RNA H19. Int J Mol Sci 2017;18(11):2319. DOI: 10.3390/ijms18112319Nie W., Ge H.J., Yang X.Q. et al. LncRNA-UCA1 exerts oncogenic functions in non-small cell lung cancer by targeting miR-193a-3p. Cancer Lett 2016;371(1):99–106. DOI: 10.1016/j.canlet.2015.11.024Hsiao K.Y., Lin Y.C., Gupta S.K. et al. noncoding effects of circular RNA CCDC66 promote colon cancer growth and Metastasis. Cancer Res 2017;77(9):2339–50. DOI: 10.1158/0008-5472.CAN-16-1883Yu J., Xu Q.G., Wang Z.G. et al. Circular RNA cSMARCA5 inhibits growth and metastasis in hepatocellular carcinoma. J Hepatol 2018;68(6):1214–27. DOI: 10.1016/j.jhep.2018.01.01Hou P., Zhao Y., Li Z. et al. LincRNA-ROR induces epithelial-to-mesenchymal transition and contributes to breast cancer tumorigenesis and metastasis. Cell Death Dis 2014;5(6):e1287. DOI: 10.1038/cddis.2014.249Jiang X., Zhou Y. NEAT1 contributes to breast cancer progression through modulating miR-448 and ZEB1. J Cell Physiol 2018;233(11):8558–66. DOI: 10.1002/jcp.26470Chou J., Wang B., Zheng T. et al. MALAT1 induced migration and invasion of human breast cancer cells by competitively binding miR-1 with cdc42. Biochem Biophys Res Commun 2016;472(1):262–9. DOI: 10.1016/j.bbrc.2016.02.102Li J., Hao Y., Mao W. LincK contributes to breast tumorigenesis by promoting proliferation and epithelial-to-mesenchymal transition. J Hematol Oncol 2019;12(1):19. DOI: 10.1186/s13045-019-0707-8Zhang G., Song W. Long non-coding RNA LSINCT5 inactivates Wnt/β -catenin pathway to regulate MCF-7 cell proliferation and motility through targeting the miR-30a. Ann Transl Med 2020;8(24):1635. DOI: 10.21037/atm-20-7253Yang X.Z., Cheng T.T., He Q.J. et al. LINC01133 as ceRNA inhibits gastric cancer progression by sponging miR-106a-3p to regulate APC expression and the Wnt/β-catenin pathway. Mol Cancer 2018;17(1):126. DOI: 10.1186/s12943-018-0874-1Guo K., Qian K., Shi Y. et al. LncRNA-MIAT promotes thyroid cancer progression and function as ceRNA to target EZH2 by sponging miR-150-5p. Cell Death Dis 2021;12(12):1097. DOI: 10.1038/s41419-021-04386-0Ma X., Ren H., Zhang Y. et al. LncRNA RHPN1-AS1 inhibition induces autophagy and apoptosis in prostate cancer cells via the miR-7-5p/EGFR/PI3K/AKT/mTOR signaling pathway. Environ Toxicol 2022;37(12):3013–27. DOI: 10.1002/tox.23656Yu Z., Che N., He Y., Zhang B. ceRNA network of lncRNA MIR210HG/miR-377-3p/LMX1A in malignant proliferation of glioma cells. Genes Genomics 2022;44(12):1445–55. DOI: 10.1007/s13258-022-01312-2Shu C., Wang W., Wu L. et al. LINC00936/microRNA-221-3p regulates tumor progression in ovarian cancer by interacting with LAMA3. Recent Pat Anticancer Drug Discov 2023;18(1):66–79. DOI: 10.2174/1574892817666220316152201Kapusta A., Feschotte C. Volatile evolution of long noncoding RNA repertoires: mechanisms and biological implication. Trends Genet 2014;30(10):439–52. DOI: 10.1016/j.tig.2014.08.004Johnson R., Guigo R. The RIDL hypothesis: transposable elements as functional domains of long noncoding RNAs. RNA 2014;20(7):959–76. DOI: 10.1261/rna.044560Kapusta A., Kronenberg Z., Lynch V.J. et al. Transposable elements are major contributors to the origin, diversification, and regulation of vertebrate long noncgoding RNAs. PLoS Genet 2013;9(4):e1003470. DOI: 10.1371/journal.pgen.1003470Honson D.D., Macfarlan T.S. A lncRNA-like role for LINE-1s in development. Dev Cell 2018;46(2):132–4. DOI: 10.1016/j.devcel.2018.06.022Zhou B., Yang H., Yang C. et al. Translation of noncoding RNAs and cancer. Cancer Lett 2021;497:89–99. DOI: 10.1016/j.canlet.2020.10.002Godet Y., Moreau-Aubry A., Guilloux Y. et al. MELOE-1 is a new antigen overexpressed in melanomas and involved in adoptive T cell transfer efficiency. J Exp Med 2008;205(11):2673–82. DOI: 10.1084/jem.20081356.Charpentier M., Croyal M., Carbonnelle D. et al. IRES-dependent translation of the long non coding RNA meloe in melanoma cells produces the most immunogenic MELOE antigens. Oncotarget 2016;7(37):59704–13. DOI: 10.18632/oncotarget.10923Szafron L.M., Balcerak A., Grzybowska E.A. et al. The novel gene journal pre-proof 25 CRNDE encodes a nuclear peptide (CRNDEP) which is overexpressed in highly proliferating tissues. PLoS One 2015;10(5):e0127475. DOI: 10.1371/journal.pone.0127475Fang J., Morsalin S., Rao V.N., Reddy E.S.P. Decoding of non-coding DNA and non-coding RNA: pri-micro RNA-encoded novel peptides regulate migration of cancer cells. J Pharm Sci Pharmacol 2017;3:23–7.Kang M., Tang B., Li J. et al. Identification of miPEP133 as a novel tumor-suppressor microprotein encoded by miR-34a pri-miRNA. Mol Cancer 2020;19:143. DOI: 10.1186/s12943-020-01248-9Huang J.Z., Chen M., Chen D. et al. A peptide encoded by a putative lncRNA HOXB-AS3 suppresses colon cancer growth. Mol Cell 2017;68(1):171–84.e6. DOI: 10.1016/j.molcel.2017.09.015D’Lima N.G., Ma J., Winkler L. et al. A human microprotein that interacts with the mRNA decapping complex. Nat Chem Biol 2017;13(2):174–80. DOI: 10.1038/nchembio.2249Zhang M., Zhao K., Xu X. et al. A peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma. Nat Commun 2018;9(1):4475. DOI: 10.1038/s41467-018-06862-2Zhang M., Huang N., Yang X. et al. A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis. Oncogene 2018;37(13):1805–14. DOI: 10.1038/s41388-017-0019-9Yang Y., Gao X., Zhang M. et al. Novel role of FBXW7 Circular RNA in repressing glioma tumorigenesis. J Natl Cancer Inst 2018;110(3):304–15. DOI: 10.1093/jnci/djx166Ye F., Gao G., Zou Y. et al. circFBXW7 inhibits malignant progression by sponging miR-197-3p and encoding a 185-aa protein in triple-negative breast cancer. Mol Ther Nucleic Acids 2019;18:88–98. DOI: 10.1016/j.omtn.2019.07.023Gu C., Zhou N., Wang Z. et al. circGprc5a promoted bladder oncogenesis and metastasis through Gprc5a-targeting peptide. Mol Ther Nucleic Acids 2018;13:633–41. DOI: 10.1016/j.omtn.2018.10.008Zheng X., Chen L., Zhou Y. et al. A novel protein encoded by a circular RNA circPPP1R12A promotes tumor pathogenesis and metastasis of colon cancer via Hippo-YAP signaling. Mol Cancer 2019;18(1):47. DOI: 10.1186/s12943-019-1010-6Pan Z., Cai J., Lin J. et al. A novel protein encoded by circFNDC3B inhibits tumor progression and EMT through regulating Snail in colon cancer. Mol Cancer 2020;19(1):71. DOI: 10.1186/s12943-020-01179-5Liang W.C., Wong C.W., Liang P.P. et al. Translation of the circular RNA circbeta-catenin promotes liver cancer cell growth through activation of the Wnt pathway. Genome Biol 2019;20(1):84. DOI: 10.1186/s13059-019-1685-4Guo B., Wu S., Zhu X. et al. Micropeptide CIP2A-BP encoded by LINC00665 inhibits triple-negative breast cancer progression. Embo J 2020;39(1):e102190. DOI: 10.15252/embj.2019102190Wang Y., Wu S., Zhu X. et al. LncRNA-encoded polypeptide ASRPS inhibits triple-negative breast cancer angiogenesis. J Exp Med 2020;217(3):jem.20190950. DOI: 10.1084/jem.20190950Meng N., Chen M., Chen D. et al. Small protein hidden in lncRNA LOC90024 promotes “cancerous” RNA splicing and tumorigenesis. Advanced Sci (Weinh) 2020;7(10):1903233. DOI: 10.1002/advs.201903233Zhu S., Wang J.Z., Chen D. et al. An oncopeptide regulates m(6)A recognition by the m(6)A reader IGF2BP1 and tumorigenesis. Nat Commun 2020;11(1):1685. DOI: 10.1038/s41467-020-15403-9Pang Y., Liu Z., Han H. et al. Peptide SMIM30 promotes HCC development by inducing SRC/YES1 membrane anchoring and MAPK pathway activation. J Hepatol 2020;73(5):1155–69. DOI: 10.1016/j.jhep.2020.05.028Xiao X., Wang X., Wang Y. et al. Multi-functional peptide-microRNA nanocomplex for targeted microrna delivery and function imaging. Chemistry 2018;24(9):2277–85. DOI: 10.1002/chem.201705695