{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T13:18:10Z","timestamp":1789823890100,"version":"4.0.1"},"reference-count":38,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,18]],"date-time":"2023-03-18T00:00:00Z","timestamp":1679097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004699","name":"Chung Shan Medical University Hospital","doi-asserted-by":"publisher","award":["CSH-2022-D-004"],"award-info":[{"award-number":["CSH-2022-D-004"]}],"id":[{"id":"10.13039\/501100004699","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004699","name":"Chung Shan Medical University Hospital","doi-asserted-by":"publisher","award":["CSMU-CCH-111-10"],"award-info":[{"award-number":["CSMU-CCH-111-10"]}],"id":[{"id":"10.13039\/501100004699","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004699","name":"Chung Shan Medical University Hospital","doi-asserted-by":"publisher","award":["CMU111-MF-68"],"award-info":[{"award-number":["CMU111-MF-68"]}],"id":[{"id":"10.13039\/501100004699","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004699","name":"Chung Shan Medical University Hospital","doi-asserted-by":"publisher","award":["109-2314-B-040-007"],"award-info":[{"award-number":["109-2314-B-040-007"]}],"id":[{"id":"10.13039\/501100004699","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chung Shan Medical University and Changhua Christian Hospital","award":["CSH-2022-D-004"],"award-info":[{"award-number":["CSH-2022-D-004"]}]},{"name":"Chung Shan Medical University and Changhua Christian Hospital","award":["CSMU-CCH-111-10"],"award-info":[{"award-number":["CSMU-CCH-111-10"]}]},{"name":"Chung Shan Medical University and Changhua Christian Hospital","award":["CMU111-MF-68"],"award-info":[{"award-number":["CMU111-MF-68"]}]},{"name":"Chung Shan Medical University and Changhua Christian Hospital","award":["109-2314-B-040-007"],"award-info":[{"award-number":["109-2314-B-040-007"]}]},{"name":"China Medical University","award":["CSH-2022-D-004"],"award-info":[{"award-number":["CSH-2022-D-004"]}]},{"name":"China Medical University","award":["CSMU-CCH-111-10"],"award-info":[{"award-number":["CSMU-CCH-111-10"]}]},{"name":"China Medical University","award":["CMU111-MF-68"],"award-info":[{"award-number":["CMU111-MF-68"]}]},{"name":"China Medical University","award":["109-2314-B-040-007"],"award-info":[{"award-number":["109-2314-B-040-007"]}]},{"name":"Ministry of Science and Technology","award":["CSH-2022-D-004"],"award-info":[{"award-number":["CSH-2022-D-004"]}]},{"name":"Ministry of Science and Technology","award":["CSMU-CCH-111-10"],"award-info":[{"award-number":["CSMU-CCH-111-10"]}]},{"name":"Ministry of Science and Technology","award":["CMU111-MF-68"],"award-info":[{"award-number":["CMU111-MF-68"]}]},{"name":"Ministry of Science and Technology","award":["109-2314-B-040-007"],"award-info":[{"award-number":["109-2314-B-040-007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Oral submucous fibrosis (OSF) has been recognized as a potentially malignant disorder and is characterized by inflammation and the deposition of collagen. Among various regulators of fibrogenesis, microRNAs (miR) have received great attention but the detailed mechanisms underlying the miR-mediated modulations remain largely unknown. Here, we showed that miR-424 was aberrantly overexpressed in OSF tissues, and then we assessed its functional role in the maintenance of myofibroblast characteristics. Our results demonstrated that the suppression of miR-424 markedly reduced various myofibroblast activities (such as collagen contractility and migration ability) and downregulated the expression of fibrosis markers. Moreover, we showed that miR-424 exerted this pro-fibrosis property via direct binding to TGIF2, an endogenous repressor of the TGF-\u03b2 signaling. In addition, our findings indicated that overexpression of miR-424 activated the TGF-\u03b2\/Smad pathway, leading to enhanced myofibroblast activities. Altogether, our data revealed how miR-424 contributed to myofibroblast transdifferentiation, and targeting the miR-424\/TGIF2 axis may be a viable direction for achieving satisfactory results from OSF treatment.<\/jats:p>","DOI":"10.3390\/ijms24065811","type":"journal-article","created":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T04:33:31Z","timestamp":1679286811000},"page":"5811","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["MiR-424\/TGIF2-Mediated Pro-Fibrogenic Responses in Oral Submucous Fibrosis"],"prefix":"10.3390","volume":"24","author":[{"given":"Ming-Yung","family":"Chou","sequence":"first","affiliation":[{"name":"School of Dentistry, Chung Shan Medical University, Taichung 40201, Taiwan"},{"name":"Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4190-6795","authenticated-orcid":false,"given":"Pei-Ling","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Medicine, China Medical University, Taichung 404333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0920-9340","authenticated-orcid":false,"given":"Shih-Chi","family":"Chao","sequence":"additional","affiliation":[{"name":"Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan"},{"name":"Department of Medical Research and Education, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan 265, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Wen","family":"Liao","sequence":"additional","affiliation":[{"name":"Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan"},{"name":"Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Chia","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Dentistry, Chung Shan Medical University, Taichung 40201, Taiwan"},{"name":"Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan"},{"name":"Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Yi","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, Changhua Christian Hospital, Changhua 500, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1002\/cncr.23183","article-title":"Poor prognosis in patients with stage I and II oral tongue squamous cell carcinoma","volume":"112","author":"Rusthoven","year":"2008","journal-title":"Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1158\/1055-9965.EPI-22-0642","article-title":"The Current Burden of Oropharyngeal Cancer: A Global Assessment Based on GLOBOCAN 2020","volume":"31","author":"Lorenzoni","year":"2022","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1097\/CEJ.0000000000000575","article-title":"A systematic review on the mechanisms of malignant transformation of oral submucous fibrosis","volume":"29","author":"Phulari","year":"2020","journal-title":"Eur. J. Cancer Prev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1111\/j.1600-0714.1995.tb01156.x","article-title":"Etiology of oral submucous fibrosis with special reference to the role of areca nut chewing","volume":"24","author":"Murti","year":"1995","journal-title":"J. Oral. Pathol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1111\/jcmm.12219","article-title":"Arecoline-induced myofibroblast transdifferentiation from human buccal mucosal fibroblasts is mediated by ZEB1","volume":"18","author":"Chang","year":"2014","journal-title":"J. Cell. Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5","DOI":"10.7603\/s40681-016-0005-5","article-title":"M2 macrophage polarization modulates epithelial-mesenchymal transition in cisplatin-induced tubulointerstitial fibrosis","volume":"6","author":"Yu","year":"2016","journal-title":"Biomedicine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1513\/pats.200601-004TK","article-title":"Epithelial origin of myofibroblasts during fibrosis in the lung","volume":"3","author":"Willis","year":"2006","journal-title":"Proc Am Thorac Soc"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Pant, I., Kumar, N., Khan, I., Rao, S.G., and Kondaiah, P. (2015). Role of Areca Nut Induced TGF-\u03b2 and Epithelial-Mesenchymal Interaction in the Pathogenesis of Oral Submucous Fibrosis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0129252"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Khan, I., Kumar, N., Pant, I., Narra, S., and Kondaiah, P. (2012). Activation of TGF-\u03b2 pathway by areca nut constituents: A possible cause of oral submucous fibrosis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0051806"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6721","DOI":"10.1002\/jcp.27418","article-title":"Slug mediates myofibroblastic differentiation to promote fibrogenesis in buccal mucosa","volume":"234","author":"Fang","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1111\/j.1600-0765.2008.01176.x","article-title":"Regulation of oxidative-stress responsive genes by arecoline in human keratinocytes","volume":"44","author":"Thangjam","year":"2009","journal-title":"J. Periodontal Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.freeradbiomed.2009.09.026","article-title":"Oxidative stress and glutathione in TGF-beta-mediated fibrogenesis","volume":"48","author":"Liu","year":"2010","journal-title":"Free Radic Biol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1210\/me.2010-0340","article-title":"ROS signaling by NOX4 drives fibroblast-to-myofibroblast differentiation in the diseased prostatic stroma","volume":"25","author":"Sampson","year":"2011","journal-title":"Mol. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1038\/ki.2010.516","article-title":"Myofibroblast differentiation during fibrosis: Role of NAD(P)H oxidases","volume":"79","author":"Barnes","year":"2011","journal-title":"Kidney Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.cell.2005.07.031","article-title":"Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation","volume":"122","author":"Bagga","year":"2005","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.abb.2014.12.007","article-title":"Regulation of myofibroblast differentiation by miR-424 during epithelial-to-mesenchymal transition","volume":"566","author":"Xiao","year":"2015","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"114172","DOI":"10.1016\/j.bcp.2020.114172","article-title":"TGF-\u03b21-induced miR-424 promotes pulmonary myofibroblast differentiation by targeting Slit2 protein expression","volume":"180","author":"Huang","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1161\/STROKEAHA.114.007482","article-title":"MicroRNA-424 protects against focal cerebral ischemia and reperfusion injury in mice by suppressing oxidative stress","volume":"46","author":"Liu","year":"2015","journal-title":"Stroke"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.molonc.2016.03.001","article-title":"IL-8 induces miR-424-5p expression and modulates SOCS2\/STAT5 signaling pathway in oral squamous cell carcinoma","volume":"10","author":"Peng","year":"2016","journal-title":"Mol. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Peng, C.Y., Liao, Y.W., Lu, M.Y., Yang, C.M., Hsieh, P.L., and Yu, C.C. (2020). Positive Feedback Loop of SNAIL-IL-6 Mediates Myofibroblastic Differentiation Activity in Precancerous Oral Submucous Fibrosis. Cancers, 12.","DOI":"10.2139\/ssrn.3569822"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1016\/S0002-9440(10)61776-2","article-title":"Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation","volume":"159","author":"Hinz","year":"2001","journal-title":"Am. J. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"128","DOI":"10.3389\/fmolb.2020.00128","article-title":"The Post-translational Modifications of Smurf2 in TGF-\u03b2 Signaling","volume":"7","author":"Bai","year":"2020","journal-title":"Front. Mol. Biosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1681\/ASN.2015040356","article-title":"Recombinant N-Terminal Slit2 Inhibits TGF-\u03b2-Induced Fibroblast Activation and Renal Fibrosis","volume":"27","author":"Yuen","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"32109","DOI":"10.1074\/jbc.M103377200","article-title":"TGIF2 interacts with histone deacetylase 1 and represses transcription","volume":"276","author":"Melhuish","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1016\/j.bbamcr.2007.05.016","article-title":"Histone deacetylase 4 is required for TGFbeta1-induced myofibroblastic differentiation","volume":"1773","author":"Glenisson","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_26","first-page":"974","article-title":"Role of 5\u2032TG3\u2032-interacting factors (TGIFs) in Vorinostat (HDAC inhibitor)-mediated Corneal Fibrosis Inhibition","volume":"21","author":"Sharma","year":"2015","journal-title":"Mol. Vis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6890423","DOI":"10.1155\/2021\/6890423","article-title":"MicroRNA-34a Promotes EMT and Liver Fibrosis in Primary Biliary Cholangitis by Regulating TGF-\u03b21\/smad Pathway","volume":"2021","author":"Pan","year":"2021","journal-title":"J. Immunol. Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Saso, L., Reza, A., Ng, E., Nguyen, K., Lin, S., Zhang, P., Fantozzi, P.J., Armagan, G., Romeo, U., and Cirillo, N. (2022). A Comprehensive Analysis of the Role of Oxidative Stress in the Pathogenesis and Chemoprevention of Oral Submucous Fibrosis. Antioxidants, 11.","DOI":"10.3390\/antiox11050868"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1007\/s13258-021-01103-1","article-title":"Long non-coding RNA NEAT1 promotes lipopolysaccharide-induced acute lung injury by regulating miR-424-5p\/MAPK14 axis","volume":"43","author":"Zhang","year":"2021","journal-title":"Genes Genom."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3000605211037495","DOI":"10.1177\/03000605211037495","article-title":"The lncRNA CASC9 alleviates lipopolysaccharide-induced acute kidney injury by regulating the miR-424-5p\/TXNIP pathway","volume":"49","author":"Fan","year":"2021","journal-title":"J. Int. Med. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"123400","DOI":"10.1016\/j.ijbiomac.2023.123400","article-title":"XIST\/let-7i\/HMGA1 axis maintains myofibroblasts activities in oral submucous fibrosis","volume":"232","author":"Yu","year":"2023","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.jds.2021.09.004","article-title":"miR-21 promotes the fibrotic properties in oral mucosa through targeting PDCD4","volume":"17","author":"Liao","year":"2022","journal-title":"J. Dent. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1016\/j.jds.2021.11.001","article-title":"microRNA-1266-5p directly targets DAB2IP to enhance oncogenicity and metastasis in oral cancer","volume":"17","author":"Peng","year":"2022","journal-title":"J. Dent. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.jfma.2015.05.009","article-title":"Elevation of Twist expression by arecoline contributes to the pathogenesis of oral submucous fibrosis","volume":"115","author":"Lee","year":"2016","journal-title":"J. Formos. Med. Assoc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1016\/j.jfma.2021.08.014","article-title":"Galectin-7 promotes proliferation and wound healing capacities in periodontal ligament fibroblasts by activating ERK signaling","volume":"121","author":"Huang","year":"2022","journal-title":"J. Formos. Med. Assoc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.jfma.2021.06.028","article-title":"Depletion of miR-155 hinders the myofibroblast activities and reactive oxygen species generation in oral submucous fibrosis","volume":"121","author":"Chou","year":"2022","journal-title":"J. Formos. Med. Assoc."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Lee, Y.H., Liao, Y.W., Lu, M.Y., Hsieh, P.L., and Yu, C.C. (2021). LINC00084\/miR-204\/ZEB1 Axis Mediates Myofibroblastic Differentiation Activity in Fibrotic Buccal Mucosa Fibroblasts: Therapeutic Target for Oral Submucous Fibrosis. J. Pers. Med., 11.","DOI":"10.3390\/jpm11080707"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.1016\/j.jfma.2021.04.012","article-title":"Honokiol inhibits arecoline-induced oral fibrogenesis through transforming growth factor-beta\/Smad2\/3 signaling inhibition","volume":"120","author":"Chen","year":"2021","journal-title":"J. Formos. Med. Assoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5811\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:58:16Z","timestamp":1760122696000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5811"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,18]]},"references-count":38,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24065811"],"URL":"https:\/\/doi.org\/10.3390\/ijms24065811","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,18]]}}}