{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T09:05:29Z","timestamp":1771232729581,"version":"3.50.1"},"reference-count":50,"publisher":"PeerJ","license":[{"start":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T00:00:00Z","timestamp":1771200000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Basic Research Program at the National Research University Higher School of Economics"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>MicroRNAs (miRNAs) and their isoforms, known as isomiRs, are important regulators of tumorigenesis that act as post-transcriptional modulators of gene expression. Among these, 5\u2019-isomiRs\u2014generated through imprecise cleavage during miRNA biogenesis\u2014exhibit altered seed regions compared to their canonical counterparts, potentially leading to distinct targetomes. Consequently, 5\u2019-isomiRs may exert biological functions that differ substantially from those of the corresponding canonical miRNAs. Despite growing recognition of their potential significance, the functional roles of 5\u2019-isomiRs remain largely uncharacterized for most miRNAs. In this study, we investigated the targetome divergence between canonical miRNAs and their 5\u2019-isomiRs, focusing on hsa-miR-93-5p, a miRNA with a well-established oncogenic role in prostate adenocarcinoma. Target transcripts of the 5\u2019-isomiRs were identified using a shRNA-based overexpression system. Bioinformatic analysis revealed a substantial overlap between the targets of the 5\u2019-isomiRs and the canonical miRNA. This overlap was attributed to the co-occurrence of both canonical and shifted seed motifs within the same mRNA targets. Notably, hsa-miR-93-5p ranked among the top miRNAs with a relatively high number of targets transcripts containing both seed motifs, suggesting a unique dual-targeting capacity.<\/jats:p>","DOI":"10.7717\/peerj.20642","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T08:06:22Z","timestamp":1771229182000},"page":"e20642","source":"Crossref","is-referenced-by-count":0,"title":["Targetome profile of hsa-miR-93-5p is resistant to isoform formation in prostate adenocarcinoma"],"prefix":"10.7717","volume":"14","author":[{"given":"Anton","family":"Zhiyanov","sequence":"first","affiliation":[{"name":"Faculty of Biology and Biotechnology, Higher School of Economics, Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Kirillov","sequence":"additional","affiliation":[{"name":"Faculty of Biology and Biotechnology, Higher School of Economics, Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roman","family":"Suvorov","sequence":"additional","affiliation":[{"name":"Faculty of Biology and Biotechnology, Higher School of Economics, Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Maltseva","sequence":"additional","affiliation":[{"name":"Faculty of Biology and Biotechnology, Higher School of Economics, Moscow, Russia"},{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Tonevitsky","sequence":"additional","affiliation":[{"name":"Faculty of Biology and Biotechnology, Higher School of Economics, Moscow, Russia"},{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"4443","published-online":{"date-parts":[[2026,2,16]]},"reference":[{"key":"10.7717\/peerj.20642\/ref-1","doi-asserted-by":"publisher","DOI":"10.7554\/elife.05005","article-title":"Predicting effective microRNA target sites in mammalian mRNAs","volume":"4","author":"Agarwal","year":"2015","journal-title":"ELife"},{"issue":"D1","key":"10.7717\/peerj.20642\/ref-2","doi-asserted-by":"publisher","first-page":"D179","DOI":"10.1093\/nar\/gkac884","article-title":"isomiRdb: microRNA expression at isoform resolution","volume":"51","author":"Aparicio-Puerta","year":"2022","journal-title":"Nucleic Acids Research"},{"issue":"9","key":"10.7717\/peerj.20642\/ref-3","doi-asserted-by":"publisher","first-page":"e73240","DOI":"10.1371\/journal.pone.0073240","article-title":"Beta cell 5\u2032-shifted isomiRs are candidate regulatory hubs in type 2 diabetes","volume":"8","author":"Baran-Gale","year":"2013","journal-title":"PLOS ONE"},{"issue":"2","key":"10.7717\/peerj.20642\/ref-4","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.cell.2009.01.002","article-title":"MicroRNAs: target recognition and regulatory functions","volume":"136","author":"Bartel","year":"2009","journal-title":"Cell"},{"issue":"33","key":"10.7717\/peerj.20642\/ref-5","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202402954","article-title":"piRNA PROPER suppresses DUSP1 translation by targeting N6-methyladenosine-mediated RNA circularization to promote oncogenesis of prostate cancer","volume":"11","author":"Ben","year":"2024","journal-title":"Advanced Science"},{"issue":"1","key":"10.7717\/peerj.20642\/ref-6","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-018-1074-z","article-title":"The isomiR-140-3p-regulated mevalonic acid pathway as a potential target for prevention of triple negative breast cancer","volume":"20","author":"Bhardwaj","year":"2018","journal-title":"Breast Cancer Research"},{"issue":"3","key":"10.7717\/peerj.20642\/ref-7","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA: A Cancer Journal for Clinicians"},{"key":"10.7717\/peerj.20642\/ref-8","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2018.00045","article-title":"Cell-based reporter system for high-throughput screening of microrna pathway inhibitors and its limitations","volume":"9","author":"Brustikova","year":"2018","journal-title":"Frontiers in Genetics"},{"issue":"1","key":"10.7717\/peerj.20642\/ref-9","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-15-29","article-title":"A tool for design of primers for microRNA-specific quantitative RT-qPCR","volume":"15","author":"Busk","year":"2014","journal-title":"BMC Bioinformatics"},{"issue":"D1","key":"10.7717\/peerj.20642\/ref-10","doi-asserted-by":"publisher","first-page":"D127","DOI":"10.1093\/nar\/gkz757","article-title":"miRDB: an online database for prediction of functional microRNA targets","volume":"48","author":"Chen","year":"2019","journal-title":"Nucleic Acids Research"},{"issue":"3","key":"10.7717\/peerj.20642\/ref-11","doi-asserted-by":"publisher","first-page":"a032771","DOI":"10.1101\/cshperspect.a032771","article-title":"Mechanistic insights into MicroRNA-mediated gene silencing","volume":"11","author":"Duchaine","year":"2018","journal-title":"Cold Spring Harbor Perspectives in Biology"},{"issue":"1","key":"10.7717\/peerj.20642\/ref-12","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1002\/1878-0261.13535","article-title":"Spontaneous metastasis xenograft models link CD44 isoform 4 to angiogenesis, hypoxia, EMT and mitochondria-related pathways in colorectal cancer","volume":"18","author":"Everest-Dass","year":"2023","journal-title":"Molecular Oncology"},{"key":"10.7717\/peerj.20642\/ref-13","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.omtn.2017.11.006","article-title":"Delineation of the exact transcription termination signal for type 3 polymerase III","volume":"10","author":"Gao","year":"2018","journal-title":"Molecular Therapy\u2014Nucleic Acids"},{"key":"10.7717\/peerj.20642\/ref-14","doi-asserted-by":"publisher","first-page":"2260","DOI":"10.18502\/ijph.v52i11.14026","article-title":"Diagnostic and prognostic value of mir-93 in prostate cancer: a meta-analysis and bioinformatics analysis","volume":"52","author":"Gazzaz","year":"2023","journal-title":"Iranian Journal of Public Health"},{"issue":"1","key":"10.7717\/peerj.20642\/ref-15","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/s41580-018-0045-7","article-title":"Regulation of microRNA function in animals","volume":"20","author":"Gebert","year":"2018","journal-title":"Nature Reviews Molecular Cell Biology"},{"issue":"1","key":"10.7717\/peerj.20642\/ref-16","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-01373-9","article-title":"Role of circulating MicroRNAs in prostate cancer diagnosis and risk stratification in the MCC Spain study","volume":"15","author":"G\u00f3mez-Acebo","year":"2025","journal-title":"Scientific Reports"},{"issue":"5","key":"10.7717\/peerj.20642\/ref-17","doi-asserted-by":"publisher","first-page":"e0154955","DOI":"10.1371\/journal.pone.0154955","article-title":"A comprehensive analysis of miRNA\/isomiR expression with gender difference","volume":"11","author":"Guo","year":"2016","journal-title":"PLOS ONE"},{"issue":"5871","key":"10.7717\/peerj.20642\/ref-18","doi-asserted-by":"publisher","first-page":"1785","DOI":"10.1126\/science.1151651","article-title":"Gene regulation by transcription factors and MicroRNAs","volume":"319","author":"Hobert","year":"2008","journal-title":"Science"},{"key":"10.7717\/peerj.20642\/ref-19","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.702695","article-title":"Identification and elucidation of the protective isomiRs in lung cancer patient prognosis","volume":"12","author":"Hsieh","year":"2021","journal-title":"Frontiers in Genetics"},{"issue":"8","key":"10.7717\/peerj.20642\/ref-20","doi-asserted-by":"publisher","first-page":"3358","DOI":"10.7150\/ijbs.68221","article-title":"The regulatory function of piRNA\/PIWI complex in cancer and other human diseases: the role of DNA methylation","volume":"18","author":"Jia","year":"2022","journal-title":"International Journal of Biological Sciences"},{"issue":"D1","key":"10.7717\/peerj.20642\/ref-21","doi-asserted-by":"publisher","first-page":"D211","DOI":"10.1093\/nar\/gkab808","article-title":"miRNATissueAtlas2: an update to the human miRNA tissue atlas","volume":"50","author":"Keller","year":"2021","journal-title":"Nucleic Acids Research"},{"issue":"13","key":"10.7717\/peerj.20642\/ref-22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1602532113","article-title":"Re-evaluation of the roles of DROSHA, exportin 5, and DICER in microRNA biogenesis","volume":"113","author":"Kim","year":"2016","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"1","key":"10.7717\/peerj.20642\/ref-23","doi-asserted-by":"publisher","DOI":"10.1038\/srep45197","article-title":"Dissecting miRNA gene repression on single cell level with an advanced fluorescent reporter system","volume":"7","author":"Lemus-Diaz","year":"2017","journal-title":"Scientific Reports"},{"issue":"1","key":"10.7717\/peerj.20642\/ref-24","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-022-02380-8","article-title":"5\u2019isomiR-183-5p\u2014+2 elicits tumor suppressor activity in a negative feedback loop with E2F1","volume":"41","author":"Li","year":"2022","journal-title":"Journal of Experimental & Clinical Cancer Research"},{"key":"10.7717\/peerj.20642\/ref-25","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.omto.2018.08.001","article-title":"miR-93 promotes the growth and invasion of prostate cancer by upregulating its target genes TGFBR2, ITGB8, and LATS2","volume":"11","author":"Liu","year":"2018","journal-title":"Molecular Therapy\u2014Oncolytics"},{"issue":"4","key":"10.7717\/peerj.20642\/ref-26","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2-\u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"issue":"13","key":"10.7717\/peerj.20642\/ref-27","doi-asserted-by":"publisher","first-page":"1828","DOI":"10.1093\/bioinformatics\/btab016","article-title":"IsoMiRmap: fast, deterministic and exhaustive mining of isomiRs from short RNA-seq datasets","volume":"37","author":"Loher","year":"2021","journal-title":"Bioinformatics"},{"issue":"18","key":"10.7717\/peerj.20642\/ref-28","doi-asserted-by":"publisher","first-page":"8790","DOI":"10.18632\/oncotarget.2405","article-title":"IsomiR expression profiles in human lymphoblastoid cell lines exhibit population and gender dependencies","volume":"5","author":"Loher","year":"2014","journal-title":"Oncotarget"},{"issue":"12","key":"10.7717\/peerj.20642\/ref-29","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biology"},{"issue":"1","key":"10.7717\/peerj.20642\/ref-30","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-025-02170-6","article-title":"Enhancer transcription profiling reveals an enhancer RNA-driven ferroptosis and new therapeutic opportunities in prostate cancer","volume":"10","author":"Ma","year":"2025","journal-title":"Signal Transduction and Targeted Therapy"},{"issue":"3","key":"10.7717\/peerj.20642\/ref-31","doi-asserted-by":"publisher","first-page":"195046","DOI":"10.1016\/j.bbagrm.2024.195046","article-title":"Incautious design of shRNAs for stable overexpression of miRNAs could result in generation of undesired isomiRs","volume":"1867","author":"Maltseva","year":"2024","journal-title":"Biochimica Et Biophysica Acta (BBA)\u2014Gene Regulatory Mechanisms"},{"key":"10.7717\/peerj.20642\/ref-32","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.biochi.2020.04.016","article-title":"Knockdown of the \u03b15 laminin chain affects differentiation of colorectal cancer cells and their sensitivity to chemotherapy","volume":"174","author":"Maltseva","year":"2020","journal-title":"Biochimie"},{"issue":"D1","key":"10.7717\/peerj.20642\/ref-33","doi-asserted-by":"publisher","first-page":"D966","DOI":"10.1093\/nar\/gkae1078","article-title":"GENCODE 2025: reference gene annotation for human and mouse","volume":"53","author":"Mudge","year":"2024","journal-title":"Nucleic Acids Research"},{"issue":"11","key":"10.7717\/peerj.20642\/ref-34","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1016\/j.tig.2012.07.005","article-title":"IsomiRs\u2014the overlooked repertoire in the dynamic microRNAome","volume":"28","author":"Neilsen","year":"2012","journal-title":"Trends in Genetics"},{"key":"10.7717\/peerj.20642\/ref-35","doi-asserted-by":"publisher","first-page":"e14205","DOI":"10.7717\/peerj.14205","article-title":"isomiRTar: a comprehensive portal of pan-cancer 5\u2032-isomiR targeting","volume":"10","author":"Nersisyan","year":"2022","journal-title":"PeerJ"},{"key":"10.7717\/peerj.20642\/ref-36","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.1070528","article-title":"A novel approach for a joint analysis of isomiR and mRNA expression data reveals features of isomiR targeting in breast cancer","volume":"13","author":"Nersisyan","year":"2022","journal-title":"Frontiers in Genetics"},{"issue":"5","key":"10.7717\/peerj.20642\/ref-37","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.tig.2007.02.011","article-title":"Mechanisms of microRNA-mediated gene regulation in animal cells","volume":"23","author":"Nilsen","year":"2007","journal-title":"Trends in Genetics"},{"issue":"12","key":"10.7717\/peerj.20642\/ref-38","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1080\/15384101.2021.1930356","article-title":"Investigation of miR-93-5p and its effect on the radiosensitivity of breast cancer","volume":"20","author":"Pan","year":"2021","journal-title":"Cell Cycle"},{"issue":"6","key":"10.7717\/peerj.20642\/ref-39","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1038\/s12276-022-00792-2","article-title":"hnRNPC induces isoform shifts in miR-21-5p leading to cancer development","volume":"54","author":"Park","year":"2022","journal-title":"Experimental and Molecular Medicine"},{"issue":"1","key":"10.7717\/peerj.20642\/ref-40","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-016-2869-x","article-title":"The highly expressed 5\u2019isomiR of hsa-miR-140-3p contributes to the tumor-suppressive effects of miR-140 by reducing breast cancer proliferation and migration","volume":"17","author":"Salem","year":"2016","journal-title":"BMC Genomics"},{"issue":"6","key":"10.7717\/peerj.20642\/ref-41","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1016\/j.molcel.2010.06.005","article-title":"Expanding the MicroRNA targeting code: functional sites with centered pairing","volume":"38","author":"Shin","year":"2010","journal-title":"Molecular Cell"},{"issue":"3","key":"10.7717\/peerj.20642\/ref-42","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.molcel.2010.03.013","article-title":"Posttranscriptional regulation of MicroRNA biogenesis in animals","volume":"38","author":"Siomi","year":"2010","journal-title":"Molecular Cell"},{"issue":"4","key":"10.7717\/peerj.20642\/ref-43","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1261\/rna.2192803","article-title":"Lentivirus-delivered stable gene silencing by RNAi in primary cells","volume":"9","author":"Stewart","year":"2003","journal-title":"RNA"},{"issue":"14","key":"10.7717\/peerj.20642\/ref-44","doi-asserted-by":"publisher","first-page":"9424","DOI":"10.1093\/nar\/gku656","article-title":"5\u2032-isomiR variation is of functional and evolutionary importance","volume":"42","author":"Tan","year":"2014","journal-title":"Nucleic Acids Research"},{"issue":"1","key":"10.7717\/peerj.20642\/ref-45","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/j.ymthe.2019.10.002","article-title":"MicroRNA-411 and its 5\u2032-IsomiR have distinct targets and functions and are differentially regulated in the vasculature under Ischemia","volume":"28","author":"Van\u00a0der Kwast","year":"2020","journal-title":"Molecular Therapy"},{"issue":"9","key":"10.7717\/peerj.20642\/ref-46","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1016\/j.tig.2024.05.007","article-title":"The intricacies of isomiRs: from classification to clinical relevance","volume":"40","author":"Wagner","year":"2024","journal-title":"Trends in Genetics"},{"key":"10.7717\/peerj.20642\/ref-47","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.gene.2018.01.024","article-title":"MiR-93-5p up-regulation is involved in non-small cell lung cancer cells proliferation and migration and poor prognosis","volume":"647","author":"Yang","year":"2018","journal-title":"Gene"},{"key":"10.7717\/peerj.20642\/ref-48","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1016\/j.ijbiomac.2018.12.088","article-title":"MiR-93 functions as a tumor promoter in prostate cancer by targeting disabled homolog 2 (DAB2) and an antitumor polysaccharide from green tea (Camellia sinensis) on their expression","volume":"125","author":"Yang","year":"2019","journal-title":"International Journal of Biological Macromolecules"},{"issue":"1","key":"10.7717\/peerj.20642\/ref-49","doi-asserted-by":"publisher","DOI":"10.1007\/s12672-024-01376-4","article-title":"Recent progress in microRNA research for prostate cancer","volume":"15","author":"Yuan","year":"2024","journal-title":"Discover Oncology"},{"issue":"2","key":"10.7717\/peerj.20642\/ref-50","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btad051","article-title":"Differential co-expression network analysis with DCoNA reveals isomiR targeting aberrations in prostate cancer","volume":"39","author":"Zhiyanov","year":"2023","journal-title":"Bioinformatics"}],"container-title":["PeerJ"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/peerj.com\/articles\/20642.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/peerj.com\/articles\/20642.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/peerj.com\/articles\/20642.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/peerj.com\/articles\/20642.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T08:06:25Z","timestamp":1771229185000},"score":1,"resource":{"primary":{"URL":"https:\/\/peerj.com\/articles\/20642"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,16]]},"references-count":50,"alternative-id":["10.7717\/peerj.20642"],"URL":"https:\/\/doi.org\/10.7717\/peerj.20642","archive":["CLOCKSS","LOCKSS","Portico"],"relation":{},"ISSN":["2167-8359"],"issn-type":[{"value":"2167-8359","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,16]]},"article-number":"e20642"}}