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MicroRNAs (miRNAs) are able to fine-tune large-scale target genes. Here we established a simple but effective computational strategy based on available miRNA target prediction algorithms to pinpoint the most potent miRNA that could negatively regulate a group of functional genes. Based on this rationale, miR-335-3p was top ranked by putatively targeting 85 verified profibrotic genes and 79 upregulated genes in HGF patients. Experimentally, downregulation of miR-355-3p was demonstrated in HGF-derived gingival fibroblasts as well as in transforming growth factor \u03b2\u2013stimulated normal human gingival fibroblasts (NHGFs) compared to normal control. Ectopic miR-335-3p attenuated, whereas knockdown of miR-335-3p promoted, the fibrogenic activity of human gingival fibroblasts. Mechanically, miR-335-3p directly targeted SOS1, SMAD2\/3, and CTNNB1 by canonical and noncanonical base paring. In particular, different portfolios of fibrotic markers were suppressed by silencing SOS1, SMAD2\/3, or CTNNB1, respectively. Thus, our study first proposes a novel miRNA screening approach targeting a functionally related gene set and identifies miR-335-3p as a novel target for HGF treatment. Mechanically, miR-335-3p suppresses the fibrogenic activity of human gingival fibroblasts by repressing multiple core molecules in profibrotic networks. Our strategy provides a new paradigm in the treatment for HGF as well as other diseases.<\/jats:p>","DOI":"10.1177\/0022034519863300","type":"journal-article","created":{"date-parts":[[2019,7,19]],"date-time":"2019-07-19T18:24:08Z","timestamp":1563560648000},"page":"1140-1149","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":14,"title":["Antifibrotic Potential of MiR-335-3p in Hereditary Gingival Fibromatosis"],"prefix":"10.1177","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5300-8012","authenticated-orcid":false,"given":"Q.","family":"Gao","sequence":"first","affiliation":[{"name":"The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K.","family":"Yang","sequence":"additional","affiliation":[{"name":"The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D.","family":"Chen","sequence":"additional","affiliation":[{"name":"The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y.","family":"Song","sequence":"additional","affiliation":[{"name":"The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3955-5022","authenticated-orcid":false,"given":"W.","family":"Qiao","sequence":"additional","affiliation":[{"name":"The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"X.","family":"Sun","sequence":"additional","affiliation":[{"name":"The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L.","family":"Meng","sequence":"additional","affiliation":[{"name":"The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Z.","family":"Bian","sequence":"additional","affiliation":[{"name":"The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2019,7,19]]},"reference":[{"key":"bibr1-0022034519863300","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1734"},{"issue":"5","key":"bibr2-0022034519863300","first-page":"398","volume":"36","author":"Arvio P","year":"1999","journal-title":"J Med Genet"},{"key":"bibr3-0022034519863300","doi-asserted-by":"publisher","DOI":"10.1038\/nature07242"},{"key":"bibr4-0022034519863300","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.01.002"},{"key":"bibr5-0022034519863300","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.06.006"},{"key":"bibr6-0022034519863300","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-051X.2006.00928.x"},{"key":"bibr7-0022034519863300","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2013.09.009"},{"key":"bibr8-0022034519863300","doi-asserted-by":"crossref","unstructured":"Caja L, Dituri F, Mancarella S, Caballero-Diaz D, Moustakas A, Giannelli G, Fabregat I. 2018. 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