The Smad2/3/4 complex binds miR-139 promoter to modulate TGF-βinduced proliferation and activation of human Tenon's capsule fibroblasts through the Wnt pathway

The activation and proliferation of human Tenon's fibroblasts (HTFs) play a vital role in the fibrosis in the pathology of the scar formation after the glaucoma filtration surgery. Transforming growth factor 1 (TGF1)/Smads signaling has been reported to promote fibrosis. In our previous study, we revealed that TGF1-induced orbital fibroblast activation and proliferation through Wnt/-catenin signaling. As microRNA (miR)-139 could target several factors in Wnt signaling to modulate fibrosis, here, the effect and mechanism of miR-139 in HTF activation and proliferation were investigated. miR-139 overexpression significantly reversed the TGF1-induced increase in collagen I and -smooth muscle actin contents and proliferation in HTFs. CTNNB1 and CTNND1 were direct downstream of miR-139 and can significantly restore the suppressive effect of miR-139 on the activation and proliferation in HTFs under TGF1 stimulation. Smad2/3/4 complex inhibits the transcription activity of miR-139, most possibly by Smad4 binding to the miR-139 promoter. Taken together, we demonstrated a new mechanism of HTF activation and proliferation from the perspective of miRNA regulation, which may provide new strategies for improving the fibrosis after the glaucoma filtration surgery.