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Young Hoon Hwang, Sun-Ah Jung, Jungmook Lyu, Yong Yeon Kim, Joon H. Lee; Transforming Growth Factor-β1–induced Human Subconjunctival Fibrosis is Mediated by MicroRNA 143/145 Expression. Invest. Ophthalmol. Vis. Sci. 2019;60(6):2064-2071. doi: 10.1167/iovs.19-26797.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the roles and pathways of microRNAs 143 and 145 in transforming growth factor (TGF)-β1–induced human subconjunctival fibrosis.
Human tenon's capsule fibroblasts (HTFs) were obtained from a healthy eye. After treating cultured HTFs with TGF-β1, the expression of microRNAs 143 and 145 was evaluated using polymerase chain reaction. To identify the pathways of TGF-β1–induced microRNA 143/145 expression, HTFs were treated with specific inhibitors of p38MAPK, PI3K/Akt, JNK, ERK, and with siRNAs for SMAD2 and SMAD4. Mutagenesis studies were performed to evaluate the role of the CArG box and SMAD-binding element (SBE). To investigate the role of microRNA 143/145 in TGF-β1–induced myofibroblast transdifferentiation, microRNA 143/145 mimics and microRNA 143/145 inhibitors were applied to the HTFs.
Array analysis revealed that TGF-β1 induced the expression of microRNA 143/145 in a dose- and time-dependent manner. When inhibitors and siRNAs for p38MAPK, PI3K/Akt, ERK, and JNK were applied, the TGF-β1–induced expression of microRNA 143/145 was inhibited; however, SMAD2 and SMAD4 inhibition did not affect the TGF-β1–induced expression of these microRNAs. In the mutagenesis studies, both the CArG box and SBE were associated with TGF-β1–induced expression of microRNA 143/145. Mimics of microRNA 143/145 induced increased myofibroblast formation, whereas their inhibitors had the opposite effect.
TGF-β1–induced human subconjunctival fibrosis was mediated by the expression of microRNA 143/145, mainly via SMAD-independent pathways. Inhibition of TGF-β1–induced microRNA 143/145 expression in HTFs might represent a novel strategy to prevent subconjunctival fibrosis.
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