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 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
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DOI：
10.1002/jcp.28011
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发表时间：
2019-08-01
影响因子：
5.6
通讯作者：
Xiong, Wei
中科院分区：
文献类型：
--
作者：
Deng, Mi;Hou, Shi-Ying;Xiong, Wei
人眼球筋膜成纤维细胞（HTFs）的活化和增殖在青光眼滤过术后瘢痕形成的病理过程中起着重要的纤维化作用。已报道转化生长因子1（TGF 1）/Smads信号传导促进纤维化。在我们之前的研究中，我们发现TGF-1通过Wnt/β-catenin信号转导诱导眼眶成纤维细胞活化和增殖。由于microRNA（miR）-139可以靶向Wnt信号通路中的多个因子来调节纤维化，因此，本文研究了miR-139在HTF活化和增殖中的作用和机制。miR-139过表达显著逆转了TGF-1诱导的I型胶原和平滑肌肌动蛋白含量的增加以及HTFs的增殖。CTNNB 1和CTNND 1位于miR-139的直接下游，并可显著恢复miR-139对TGF 1刺激下HTFs活化和增殖的抑制作用。Smad 2/3/4复合物抑制miR-139的转录活性，最可能是通过Smad 4与miR-139启动子结合。综上所述，我们从miRNA调控的角度阐明了HTF活化和增殖的新机制，这可能为改善青光眼滤过手术后纤维化提供新的策略。
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.