{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T02:37:44Z","timestamp":1772764664098,"version":"3.50.1"},"reference-count":70,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,9]],"date-time":"2021-02-09T00:00:00Z","timestamp":1612828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE026767"],"award-info":[{"award-number":["R01DE026767"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE029818"],"award-info":[{"award-number":["R01DE029818"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R03DE026509"],"award-info":[{"award-number":["R03DE026509"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R03DE028340"],"award-info":[{"award-number":["R03DE028340"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cleft lip (CL) is one of the most common birth defects. It is caused by either genetic mutations or environmental factors. Recent studies suggest that environmental factors influence the expression of noncoding RNAs [e.g., microRNA (miRNA)], which can regulate the expression of genes crucial for cellular functions. In this study, we examined which miRNAs are associated with CL. Among 10 candidate miRNAs (miR-98-3p, miR-101a-3p, miR-101b-3p, miR-141-3p, miR-144-3p, miR-181a-5p, miR-196a-5p, miR-196b-5p, miR-200a-3p, and miR-710) identified through our bioinformatic analysis of CL-associated genes, overexpression of miR-181a-5p, miR-196a-5p, miR-196b-5p, and miR-710 inhibited cell proliferation through suppression of genes associated with CL in cultured mouse embryonic lip mesenchymal cells (MELM cells) and O9-1 cells, a mouse cranial neural crest cell line. In addition, we found that phenytoin, an inducer of CL, decreased cell proliferation through miR-196a-5p induction. Notably, treatment with a specific inhibitor for miR-196a-5p restored cell proliferation through normalization of expression of CL-associated genes in the cells treated with phenytoin. Taken together, our results suggest that phenytoin induces CL through miR-196a-5p induction, which suppresses the expression of CL-associated genes.<\/jats:p>","DOI":"10.3390\/ijms22041746","type":"journal-article","created":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T00:49:26Z","timestamp":1613090966000},"page":"1746","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Phenytoin Inhibits Cell Proliferation through microRNA-196a-5p in Mouse Lip Mesenchymal Cells"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0977-434X","authenticated-orcid":false,"given":"Hiroki","family":"Yoshioka","sequence":"first","affiliation":[{"name":"Department of Diagnostic &amp; Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA"},{"name":"Center for Craniofacial Research, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sai Shankar","family":"Ramakrishnan","sequence":"additional","affiliation":[{"name":"Department of Diagnostic &amp; Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA"},{"name":"Center for Craniofacial Research, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3163-8093","authenticated-orcid":false,"given":"Akiko","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Diagnostic &amp; Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA"},{"name":"Center for Craniofacial Research, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3975-6836","authenticated-orcid":false,"given":"Junichi","family":"Iwata","sequence":"additional","affiliation":[{"name":"Department of Diagnostic &amp; Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA"},{"name":"Center for Craniofacial Research, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA"},{"name":"MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2800","DOI":"10.12688\/f1000research.9503.1","article-title":"Genetic factors influencing risk to orofacial clefts: Today\u2019s challenges and tomorrow\u2019s opportunities","volume":"5","author":"Beaty","year":"2016","journal-title":"F1000Research"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1080\/15592294.2019.1581591","article-title":"Epigenomic profiling of newborns with isolated orofacial clefts reveals widespread DNA methylation changes and implicates metastable epiallele regions in disease risk","volume":"14","author":"Gonseth","year":"2019","journal-title":"Epigenetics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1097\/EDE.0b013e3182125f9c","article-title":"Risk of oral clefts in twins","volume":"22","author":"Grosen","year":"2011","journal-title":"Epidemiology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/bs.ctdb.2015.12.010","article-title":"Gene-Environment Interactions and the Etiology of Birth Defects","volume":"116","author":"Krauss","year":"2016","journal-title":"Curr. 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