MiR-3606-3p inhibits systemic sclerosis through targeting TGF-β type II receptor

作者：Xiangguang Shi, Qingmei Liu, Na Li, Wenzhen Tu, Ruoyu Luo, Xueqian Mei, Yanyun Ma, Weihong Xu, Haiyan Chu, Shuai Jiang, Zhimin Du, Zhao, Han, Liang Zhao, Jin Li, Wenyu Wu, Jiucun Wang · 发表于：Figshare · 年份：2018 · DOI：10.6084/m9.figshare.7012037 · 研究领域：Systemic Sclerosis and Related Diseases、Dermatologic Treatments and Research

Systemic sclerosis (SSc) is a multisystemic fibrotic disease characterized by excessive collagen deposition and extracellular matrix synthesis. Though transforming growth factor-β (TGF-β) plays a fundamental role in the pathogenesis of SSc, the mechanism by which TGF-β signaling acts in SSc remains largely unclear. Here, we showed that TGF-β type II receptor (TGFBR2) was significantly upregulated in both human SSc dermal tissues and primary fibroblasts. In fibroblasts, siRNA-induced knockdown of TGFBR2 resulted in a reduction of p-SMAD2/3 levels and reduced production of type I collagen. Additionally, functional experiments revealed that downregulation of TGFBR2 yielded an anti-growth effect on fibroblasts through inhibiting cell cycle progression. Further studies showed that miR-3606-3p could directly target the 3′-UTR of TGFBR2 and significantly decrease the levels of both TGFBR2 mRNA and protein. Furthermore, SSc dermal tissues and primary fibroblasts contain significantly reduced amounts of miR-3606-3p, and the overexpression of miR-3606-3p in fibroblasts replicates the phenotype of TGFBR2 downregulation. Collectively, our findings demonstrated that increased TGFBR2 could be responsible for the hyperactive TGF-β signaling observed in SSc. Moreover, we identified a pivotal role for miR-3606-3p in SSc, which acts, at least partly, through the attenuation of TGF-β signaling via TGFBR2 repression, suggesting that the regulation of miR-3606-3p/TGFBR2 could be a promising...