Choi Seung-Il, Jin Jun-Yup, Maeng Yong-Sun, Kim Tae-Im, Kim Eung Kweon
Department of Ophthalmology, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, South Korea.
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.
Biochem Biophys Res Commun. 2016 Mar 25;472(1):150-5. doi: 10.1016/j.bbrc.2016.02.086. Epub 2016 Feb 23.
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.
转化生长因子-β（TGF-β）诱导基因（TGFBI）蛋白（TGFBIp）与颗粒状角膜营养不良2型（GCD2）相关。TGFBIp水平可影响GCD2表型，但其潜在分子机制尚未完全阐明。我们研究了微小RNA（miRNA）和TGF-β在角膜成纤维细胞中对TGFBIp表达调控的作用。miR-9、miR-21和miR-181a的异位表达显著降低了TGFBIp水平。相反，TGF-β1可诱导miR-21和miR-181a的表达。在角膜成纤维细胞中，miR-21的表达比miR-9和miR-181a高10倍。此外，角膜成纤维细胞中TGF-β1的表达显著高于TGF-β2和TGF-β3，而野生型（WT）和GCD2纯合子（HO）角膜成纤维细胞中三种TGF-β形式的表达无显著差异。综上所述，这些数据表明TGFBIp表达受TGF-β正向调控，而TGF-β诱导的miR-21和miR-181a对TGFBIp表达起负向调控作用。总之，角膜成纤维细胞中的TGFBIp水平通过miR-21和miR-181a的协同作用以及Smad信号通路进行调控。对这些miRNA和TGF-β信号通路进行药理调节可能对包括GCD2在内的TGFBI相关角膜营养不良具有治疗潜力。
