miR-92a regulates TGF-β1-induced WISP1 expression in pulmonary fibrosis
miR-92a regulates TGF-β1-induced WISP1 expression in pulmonary fibrosis
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DOI：
10.1016/j.biocel.2014.06.011
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发表时间：
2014-08-01
影响因子：
4
通讯作者：
Koenigshoff, Melanie
中科院分区：
文献类型：
--
作者：
Berschneider, Barbara;Ellwanger, Daniel C.;Koenigshoff, Melanie
特发性肺纤维化（IPF）是特发性间质性肺炎最常见和最致命的形式。microRNA（miRNAs）是一种短的单链RNA，以转录后方式调节蛋白质表达，最近已被证明与IPF致病基因sis有关。我们先前已经鉴定出WNT 1诱导型信号通路蛋白1（WISP 1）是IPF中高度表达的促纤维化介质，但是导致WISP 1表达增加的潜在机制仍然难以捉摸。在这里，我们研究了WISP 1是否是miRNA调节的靶点。我们应用了一种新的监督机器学习方法，该方法预测了优先与miRNA核糖核蛋白复合物结合的人WISP 1 3 'UTR区域中的miR-30 a/d和miR-92 a靶位点。在IPF样本中，这两种miRNA均减少，而WISP 1蛋白则增加。我们进一步证明，转化生长因子（TGF）-β 1诱导WISP 1表达的原代肺成纤维细胞在体外和肺匀浆在体内。值得注意的是，miR-30 a和miR-92 a逆转了TGF-β 1诱导的肺成纤维细胞中WISP 1 mRNA的表达。此外，miR-92 a抑制增加了肺成纤维细胞中WISP 1蛋白的表达。在体内TGF-β 1依赖性肺纤维化模型中发现WISP 1和miR-92 a呈反比关系。最后，我们发现在原代IPF成纤维细胞中WISP 1表达显著增加，其与离体miR-92 a水平负相关。总之，我们的研究结果表明miR-92 a对肺纤维化中WISP 1表达的调节作用。(C)2014爱思唯尔有限公司版权所有。
Idiopathic pulmonary fibrosis (IPF) is the most common and fatal form of idiopathic interstitial pneumonia. MicroRNAs (miRNAs), short, single-stranded RNAs that regulate protein expression in a post-transcriptional manner, have recently been demonstrated to contribute to IPF pathogene,sis. We have previously identified WNT1-inducible signaling pathway protein 1 (WISP1) as a highly expressed pro-fibrotic mediator in IPF, but the underlying mechanisms resulting in increased WISP1 expression, remain elusive. Here, we investigated whether WISP1 is a target of miRNA regulation. We applied a novel supervised machine learning approach, which predicted miR-30a/d and miR-92a target sites in regions of the human WISP1 3'UTR preferentially bound by the miRNA ribonucleoprotein complex. Both miRNAs were decreased in IPF samples, whereas WISP1 protein was increased. We demonstrated further that transforming growth factor (TGF)-beta 1-induced WISP1 expression in primary lung fibroblasts in vitro and lung homogenates in vivo. Notably, miR-30a and miR-92a reversed TGF-beta 1-induced WISP1 mRNA expression in lung fibroblasts. Moreover, miR-92a inhibition increased WISP1 protein expression in lung fibroblasts. An inverse relationship for WISP1 and miR-92a was found in a TGF-beta 1 dependent lung fibrosis model in vivo. Finally, we found significantly increased WISP1 expression in primary IPF fibroblasts, which negatively correlated with miR-92a level ex vivo. Altogether, our findings indicate a regulatory role of miR-92a for WISP1 expression in pulmonary fibrosis. (C) 2014 Elsevier Ltd. All rights reserved.