YAP1/Twist promotes fibroblast activation and lung fibrosis that conferred by miR-15a loss in IPF
YAP1/Twist promotes fibroblast activation and lung fibrosis that conferred by miR-15a loss in IPF
复制标题
YAP1/Twist 促进 IPF 中 miR-15a 缺失导致的成纤维细胞活化和肺纤维化
DOI：
10.1038/s41418-018-0250-0
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发表时间：
2019-09-01
影响因子：
12.4
通讯作者：
Liang, Haihai
中科院分区：
文献类型：
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作者：
Chen, Yingzhun;Zhao, Xiaoguang;Liang, Haihai
特发性肺纤维化(IPF)是一种病因不明、缺乏有效干预措施的慢性进展性纤维性肺病。采用体外和体内研究相结合的方法，我们发现HIPPO途径中的关键效应因子YAP1的过表达促进了肺成纤维细胞的细胞增殖、迁移和胶原生成。此外，YAP1的促纤维化作用是通过与其伙伴TEAD相互作用而转录激活Twist1来实现的。相反，YAP1基因的敲除抑制了细胞外基质(ECM)的沉积，最终在体外和体内改善了肺纤维化。此外，我们构建了一个影响IPF中Hippo途径效应器表达的失调miRNA调控网络，并发现在IPF患者中显著下调的miR-15a是调节这一途径的最基本的miRNAs之一。此外，miR-15a的敲除通过靶向抑制YAP1而促进Twist的表达，从而导致成纤维细胞活化和肺纤维化。相反，miR-15a的治疗性修复抑制了肺成纤维细胞的纤维化形成，并消除了博莱曼诱导的小鼠肺纤维化。这些结果突出了miR-15a/YAP1/Twist轴在IPF中的作用，为肺纤维化的预防和治疗提供了新的策略。
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic parenchymal lung disease of unknown etiology and lack effective interventions. Using a combination of in vitro and in vivo studies, we found that overexpression of YAP1, a key effector in the Hippo pathway, promoted cell proliferation, migration, and collagen production in lung fibroblasts. Furthermore, the pro-fibrotic action of YAP1 was mediated by transcriptional activation of Twist1 through interacting with its partner TEAD. In contrast, knockdown of YAP1 inhibited extracellular matrix (ECM) deposition, which ultimately ameliorated lung fibrosis in vitro and in vivo. Additionally, we constructed a dysregulated miRNA regulatory network that affects the expression of the Hippo pathway effectors in IPF and identified miR-15a, which is significantly down-regulated in IPF patients, as one of the most essential miRNAs regulating this pathway. Moreover, knockdown of miR-15a resulted in fibroblast activation and lung fibrosis through promoting Twist expression by targeting inhibition of YAP1. In contrast, therapeutic restoration of miR-15a inhibits fibrogenesis in lung fibroblast and abrogated BLM-induced lung fibrosis in mice. These results highlight a role for miR-15a/YAP1/Twist axis in IPF that offer novel strategies for the prevention and treatment of lung fibrosis.