miR-29 Is a Major Regulator of Genes Associated with Pulmonary Fibrosis
miR-29 Is a Major Regulator of Genes Associated with Pulmonary Fibrosis
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DOI：
10.1165/rcmb.2010-0323oc
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发表时间：
2011-08-01
影响因子：
6.4
通讯作者：
Lue, Jining
中科院分区：
文献类型：
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作者：
Cushing, Leah;Kuang, Ping Ping;Lue, Jining
MicroRNA（miRNA）是一类通过抑制靶mRNA的翻译和去稳定化来调控基因表达的小分子调控RNA。越来越多的证据表明，miRNA调节与器官（如心脏、肾脏、肝脏和肺）中纤维化相关的基因。在一项大规模筛选可能参与博来霉素诱导的纤维化的miRNA的研究中，我们发现miR-29家族成员的表达在纤维化肺中显著降低。对正常肺的分析显示，miR-29存在于肺泡壁、胸膜和肺泡导管入口的间质细胞亚群中，这是肺纤维化的已知部位。miR-29水平与促纤维化靶基因的表达水平和纤维化的严重程度呈负相关。为了研究miR-29下调在肺组织中的影响，我们表征了内源性miR-29被敲低的人胎肺成纤维细胞IMR-90细胞的基因表达谱。这证实了报告的miR-29靶点（包括几种胶原蛋白）的去抑制，但也揭示了大量先前未识别的细胞外基质相关和重塑基因的上调。此外，我们发现，在这些细胞中，miR-29被转化生长因子（TGF）-β 1抑制，并且许多被TGF-β 1上调的纤维化相关基因被miR-29敲低去抑制。有趣的是，TGF-β 1和miR-29靶点的比较显示，miR-29控制着纤维化相关基因的另一个子集，包括层粘连蛋白和整合素，而不依赖于TGF-β 1。总之，这些强有力地表明miR-29在肺纤维化发病机制中的作用。miR-29可能是一个潜在的治疗该病的新靶点。
MicroRNAs (miRNA) are small regulatory RNAs that control gene expression by translational suppression and destabilization of target mRNAs. There is increasing evidence that miRNAs regulate genes associated with fibrosis in organs, such as the heart, kidney, liver, and the lung. In a large-scale screening for miRNAs potentially involved in bleomycin-induced fibrosis, we found expression of miR-29 family members significantly reduced in fibrotic lungs. Analysis of normal lungs showed the presence of miR-29 in subsets of interstitial cells of the alveolar wall, pleura, and at the entrance of the alveolar duct, known sites of pulmonary fibrosis. miR-29 levels inversely correlated with the expression levels of profibrotic target genes and the severity of the fibrosis. To study the impact of miR-29 down-regulation in the lung interstitium, we characterized gene expression profiles of human fetal lung fibroblast IMR-90 cells in which endogenous miR-29 was knocked down. This confirmed the derepression of reported miR-29 targets, including several collagens, but also revealed up-regulation of a large number of previously unrecognized extracellular matrix-associated and remodeling genes. Moreover, we found that miR-29 is suppressed by transforming growth factor (TGF)-beta 1 in these cells, and that many fibrosis-associated genes up-regulated by TGF-beta 1 are derepressed by miR-29 knockdown. Interestingly, a comparison of TGF-beta 1 and miR-29 targets revealed that miR-29 controls an additional subset of fibrosis-related genes, including laminins and integrins, independent of TGF-beta 1. Together, these strongly suggest a role of miR-29 in the pathogenesis of pulmonary fibrosis. miR-29 may be a potential new therapeutic target for this disease.