title: TGF-β regulates TGFBIp expression in corneal fibroblasts via miR-21, miR-181a, and Smad signaling.
abstract: Transforming growth factor-β (TGF-β)-induced gene (TGFBI) protein (TGFBIp) is associated with granular corneal dystrophy type 2 (GCD2). TGFBIp levels can affect GCD2 phenotypes, but the underlying molecular mechanisms have not been fully elucidated. We investigated the involvement of microRNA (miRNA) and TGF-β in the regulation of TGFBIp expression in corneal fibroblasts. Ectopic expression of miR-9, miR-21, and miR-181a significantly decreased TGFBIp levels. Conversely, expression of miR-21 and miR-181a was induced by TGF-β1. Expression of miR-21 was 10-fold higher than that of miR-9 and miR-181a in corneal fibroblasts. Additionally, TGF-β1 expression was significantly higher than that of TGF-β2 and TGF-β3 in corneal fibroblasts, whereas expression of all three TGF-β forms was not significantly different between wild-type (WT) and GCD2 homozygotes (HO) corneal fibroblasts. Taken together, these data indicate that TGFBIp expression is positively regulated by TGF-β, whereas TGF-β-induced miR-21 and miR-181a negatively regulate TGFBIp expression. In conclusion, TGFBIp levels in corneal fibroblasts are controlled via the coordinated activity of miR-21 and miR-181a and by Smad signaling. Pharmacologic modulation of these miRNAs and TGF-β signaling could have therapeutic potential for TGFBI-associated corneal dystrophy, including GCD2.
authors.affiliation: Department of Ophthalmology, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Seung-Il
authors.initials: SI
authors.lastname: Choi
authors.affiliation: Department of Ophthalmology, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Jun-Yup
authors.initials: JY
authors.lastname: Jin
authors.affiliation: Department of Ophthalmology, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Maeng
authors.affiliation: Department of Ophthalmology, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, South Korea; Institute of Vision Research, Severance Biomedical Science Institute, Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Tae-Im
authors.initials: TI
authors.lastname: Kim
authors.affiliation: Department of Ophthalmology, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, South Korea; Institute of Vision Research, Severance Biomedical Science Institute, Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea. Electronic address: eungkkim@yuhs.ac.
authors.forename: Eung Kweon
authors.initials: EK
authors.lastname: Kim
mesh_terms: D002478:Cells, Cultured; D003315:Cornea / Q000166:cytology / Q000378:metabolism*; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006720:Homozygote; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D000099222:betaIG-H3 Protein
chemical_list: D016326:Extracellular Matrix Proteins; D035683:MicroRNAs; D050505:Mutant Proteins; D012333:RNA, Messenger; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000099222:betaIG-H3 Protein; C524940:MIRN21 microRNA, human; C540193:MIrn181 microRNA, human
keywords: Corneal fibroblasts; Granular corneal dystrophy type 2; TGF-β; TGFBI; TGFBIp; microRNA