{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:27:05Z","timestamp":1787509625557,"version":"build-2736575974"},"reference-count":32,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T00:00:00Z","timestamp":1720742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Oral squamous cell carcinoma (OSCC) is a highly prevalent and aggressive malignancy, with mortality rates reaching 60%, mainly due to its excessive diagnostic delay. MiRNAs, a class of crucial epigenetic gene-expression regulators, have emerged as potential diagnostic biomarkers, with &gt;200 molecules exhibiting expressional dysregulation in OSCC. We had previously established an in silico methodology for the identification of the most disease-specific molecules by bridging genetics and epigenetics. Here, we identified the stage-specific miRNAs that govern the asymptomatic early stages of oral tumorigenesis by exploiting seed-matching and the reverse interplay between miRNA levels and their target genes\u2019 expression. Incorporating gene-expression data from our group\u2019s experimental hamster model of sequential oral oncogenesis, we bioinformatically detected the miRNAs that simultaneously target\/regulate &gt;75% of the genes that are characteristically upregulated or downregulated in the consecutive stages of hyperplasia, dysplasia, and early invasion, while exhibiting the opposite expressional dysregulation in OSCC-derived tissue and\/or saliva specimens. We found that all stages share the downregulation of miR-34a-5p, miR124-3p, and miR-125b-5p, while miR-1-3p is under-expressed in dysplasia and early invasion. The malignant early-invasion stage is distinguished by the downregulation of miR-147a and the overexpression of miR-155-5p, miR-423-3p, and miR-34a-5p. The identification of stage-specific miRNAs may facilitate their utilization as biomarkers for presymptomatic OSCC diagnosis.<\/jats:p>","DOI":"10.3390\/ijms25147642","type":"journal-article","created":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T08:47:41Z","timestamp":1720774061000},"page":"7642","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of Stage-Specific microRNAs that Govern the Early Stages of Sequential Oral Oncogenesis by Strategically Bridging Human Genetics with Epigenetics and Utilizing an Animal Model"],"prefix":"10.3390","volume":"25","author":[{"given":"Iphigenia","family":"Gintoni","sequence":"first","affiliation":[{"name":"Unit of Orofacial Genetics, 1st Department of Pediatrics, School of Medicine, National Kapodistrian University of Athens, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"},{"name":"Department of Molecular Genetics, Cephalogenetics Center, 176 72 Athens, Greece"},{"name":"Department of Oral and Maxillofacial Surgery, School of Medicine, National Kapodistrian University of Athens, Attikon Hospital, 124 62 Athens, Greece"},{"name":"University Research Institute for the Study of Genetic and Malignant Disorders in Childhood, Choremion Laboratory, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stavros","family":"Vassiliou","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, School of Medicine, National Kapodistrian University of Athens, Attikon Hospital, 124 62 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3098-5264","authenticated-orcid":false,"given":"George P.","family":"Chrousos","sequence":"additional","affiliation":[{"name":"University Research Institute for the Study of Genetic and Malignant Disorders in Childhood, Choremion Laboratory, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6695-186X","authenticated-orcid":false,"given":"Christos","family":"Yapijakis","sequence":"additional","affiliation":[{"name":"Unit of Orofacial Genetics, 1st Department of Pediatrics, School of Medicine, National Kapodistrian University of Athens, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"},{"name":"Department of Molecular Genetics, Cephalogenetics Center, 176 72 Athens, Greece"},{"name":"Department of Oral and Maxillofacial Surgery, School of Medicine, National Kapodistrian University of Athens, Attikon Hospital, 124 62 Athens, Greece"},{"name":"University Research Institute for the Study of Genetic and Malignant Disorders in Childhood, Choremion Laboratory, \u201cAghia Sophia\u201d Children\u2019s Hospital, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Cristaldi, M., Mauceri, R., Di Fede, O., Giuliana, G., Campisi, G., and Panzarella, V. (2019). Salivary Biomarkers for Oral Squamous Cell Carcinoma Diagnosis and Follow-Up: Current Status and Perspectives. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.01476"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"229","DOI":"10.12688\/f1000research.22941.1","article-title":"Oral squamous cell carcinoma: Metastasis, potentially associated malignant disorders, etiology and recent advancements in diagnosis","volume":"9","author":"Bugshan","year":"2020","journal-title":"F1000Reserch"},{"key":"ref_3","first-page":"e43235","article-title":"MicroRNA Profiling in Circulating Exosomes in Oral Squamous Cell Carcinoma: A Systematic Review","volume":"15","author":"Dinesh","year":"2023","journal-title":"Cureus"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Menditti, D., Santagata, M., Imola, G., Staglian\u00f2, S., Vitagliano, R., Boschetti, C.E., and Inchingolo, A.M. (2023). Personalized Medicine in Oral Oncology: Imaging Methods and Biological Markers to Support Diagnosis of Oral Squamous Cell Carcinoma (OSCC): A Narrative Literature Review. J. Pers. Med., 13.","DOI":"10.3390\/jpm13091397"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"248","DOI":"10.4103\/jomfp.JOMFP_107_19","article-title":"\u201cSKILL TO KILL\u201d\u2014Oral cancer and potentially premalignant oral epithelial lesions (PPOELs): A survey approach. Emerging of a new system and professionals","volume":"23","author":"Khan","year":"2019","journal-title":"J. Oral Maxillofac. Pathol."},{"key":"ref_6","first-page":"e46057","article-title":"miRNA Associated With Glucose Transporters in Oral Squamous Cell Carcinoma: A Systematic Review","volume":"15","author":"Priyadharshini","year":"2023","journal-title":"Cureus"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Abati, S., Bramati, C., Bondi, S., Lissoni, A., and Trimarchi, M. (2020). Oral Cancer and Precancer: A Narrative Review on the Relevance of Early Diagnosis. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17249160"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Gintoni, I., Vassiliou, S., Chrousos, G.P., and Yapijakis, C. (2023). Review of Disease-Specific microRNAs by Strategically Bridging Genetics and Epigenetics in Oral Squamous Cell Carcinoma. Genes, 14.","DOI":"10.20944\/preprints202307.0634.v1"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Ghosh, R.D., Pattatheyil, A., and Roychoudhury, S. (2020). Functional Landscape of Dysregulated MicroRNAs in Oral Squamous Cell Carcinoma: Clinical Implications. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.00619"},{"key":"ref_10","first-page":"851","article-title":"Alterations in miRNA expression patterns in whole blood of OSCC patients","volume":"28","author":"Ries","year":"2014","journal-title":"In Vivo"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/s13045-022-01351-y","article-title":"Liquid biopsy: Current technology and clinical applications","volume":"15","author":"Nikanjam","year":"2022","journal-title":"J. Hematol. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Adeola, H.A., Bello, I.O., Aruleba, R.T., Francisco, N.M., Adekiya, T.A., Adefuye, A.O., Ikwegbue, P.C., and Musaigwa, F. (2022). The Practicality of the Use of Liquid Biopsy in Early Diagnosis and Treatment Monitoring of Oral Cancer in Resource-Limited Settings. Cancers, 14.","DOI":"10.3390\/cancers14051139"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.omtn.2020.09.001","article-title":"The Circular RNA-miRNA Axis: A Special RNA Signature Regulatory Transcriptome as a Potential Biomarker for OSCC","volume":"22","author":"Saikishore","year":"2020","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Malhotra, S., Miras, M.C.M., Pappolla, A., Montalban, X., and Comabella, M. (2023). Liquid Biopsy in Neurological Diseases. Cells, 12.","DOI":"10.20944\/preprints202306.1940.v1"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/978-3-030-32633-3_32","article-title":"Regulatory Role of MicroRNAs in Brain Development and Function","volume":"1195","author":"Yapijakis","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1007\/978-3-030-78787-5_51","article-title":"The Role of MicroRNAs in Thrombosis","volume":"1339","author":"Yapijakis","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"104916","DOI":"10.1016\/j.oraloncology.2020.104916","article-title":"microRNAs in oral cancer: Moving from bench to bed as next generation medicine","volume":"111","author":"Kumar","year":"2020","journal-title":"Oral Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kim, S., Lee, J.W., and Park, Y.S. (2020). The Application of Next-Generation Sequencing to Define Factors Related to Oral Cancer and Discover Novel Biomarkers. Life, 10.","DOI":"10.3390\/life10100228"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.oooo.2021.07.012","article-title":"Expression of microRNA-21 in saliva and tumor tissue of patients with oral squamous cell carcinoma: A predictor of cervical lymph node metastasis","volume":"133","author":"Jadhav","year":"2022","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Al Rawi, N., Elmabrouk, N., Abu Kou, R., Mkadmi, S., Rizvi, Z., and Hamdoon, Z. (2021). The role of differentially expressed salivary microRNA in oral squamous cell carcinoma. A systematic review. Arch. Oral Biol., 125.","DOI":"10.1016\/j.archoralbio.2021.105108"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Rishabh, K., Khadilkar, S., Kumar, A., Kalra, I., Kumar, A.P., and Kunnumakkara, A.B. (2021). MicroRNAs as Modulators of Oral Tumorigenesis\u2014A Focused Review. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052561"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Erfanparast, L., Taghizadieh, M., and Shekarchi, A.A. (2022). Non-Coding RNAs and Oral Cancer: Small Molecules with Big Functions. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.914593"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"875","DOI":"10.4317\/jced.59736","article-title":"Liquid biopsy in the assessment of microRNAs in oral squamous cell carcinoma: A systematic review","volume":"14","author":"Palaia","year":"2022","journal-title":"J. Clin. Exp. Dent."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Menini, M., De Giovanni, E., Bagnasco, F., Delucchi, F., Pera, F., Baldi, D., and Pesce, P. (2021). Salivary Micro-RNA and Oral Squamous Cell Carcinoma: A Systematic Review. J. Pers. Med., 11.","DOI":"10.3390\/jpm11020101"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Manzano-Moreno, F.J., Costela-Ruiz, V.J., Garcia-Recio, E., Olmedo-Gaya, M.V., Ruiz, C., and Reyes-Botella, C. (2021). Role of Salivary MicroRNA and Cytokines in the Diagnosis and Prognosis of Oral Squamous Cell Carcinoma. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212215"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9479","DOI":"10.1007\/s11033-023-08791-w","article-title":"Emerging cell cycle related non-coding RNA biomarkers from saliva and blood for oral squamous cell carcinoma","volume":"50","author":"Kalmatte","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Mesgari, H., Esmaelian, S., Nasiri, K., Ghasemzadeh, S., Doroudgar, P., and Payandeh, Z. (2023). Epigenetic Regulation in Oral Squamous Cell Carcinoma Microenvironment: A Comprehensive Review. Cancers, 15.","DOI":"10.3390\/cancers15235600"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Dioguardi, M., Spirito, F., Iacovelli, G., Sovereto, D., Laneve, E., Laino, L., Caloro, G.A., Nabi, A.Q., Ballini, A., and Lo Muzio, L. (2023). The Potential microRNA Prognostic Signature in HNSCCs: A Systematic Review. Noncoding RNA, 9.","DOI":"10.3390\/ncrna9050054"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1002\/cncr.33393","article-title":"Ultrasensitive detection of tumor-specific mutations in saliva of patients with oral cavity squamous cell carcinoma","volume":"127","author":"Shanmugam","year":"2021","journal-title":"Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.oraloncology.2007.08.015","article-title":"The hamster model of sequential oral oncogenesis","volume":"44","author":"Vairaktaris","year":"2008","journal-title":"Oral Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.21873\/invivo.11665","article-title":"The Hamster Model of Sequential Oral Carcinogenesis: An Update","volume":"33","author":"Yapijakis","year":"2019","journal-title":"In Vivo"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/s13193-021-01431-4","article-title":"Molecular Insights into Oral Malignancy","volume":"13","author":"Deshmukh","year":"2022","journal-title":"Indian J. Surg. Oncol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/14\/7642\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:15:34Z","timestamp":1760109334000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/14\/7642"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,12]]},"references-count":32,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["ijms25147642"],"URL":"https:\/\/doi.org\/10.3390\/ijms25147642","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,12]]}}}