miR-4739 mediates pleural fibrosis by targeting bone morphogenetic protein 7
miR-4739 mediates pleural fibrosis by targeting bone morphogenetic protein 7
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miR-4739 通过靶向骨形态发生蛋白 7 介导胸膜纤维化。
DOI：
10.1016/j.ebiom.2019.02.057
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发表时间：
2019
期刊：
影响因子：
11.1
通讯作者：
Ye Hong
中科院分区：
文献类型：
--
作者：
Wang Meng;Xiong Liang;Jiang Li Juan;Lu Yu Zhi;Liu Fei;Song Lin Jie;Xiang Fei;He Xin Liang;Yu Fan;Shuai Shi Yuan;Ma Wan Li;Ye Hong
背景胸膜纤维化是指胸膜组织中基质成分的过度沉积，导致胸膜组织结构的破坏和功能障碍。在严重的情况下，胸膜纤维化的进展导致肺卡压，导致呼吸困难和呼吸衰竭。方法采用miRNA芯片和实时荧光定量PCR技术检测胸膜纤维化中smiR-4739的表达水平。采用实时荧光定量PCR、免疫印迹和免疫荧光技术检测纤维化相关指标的表达谱。采用双荧光素酶报告基因检测系统检测miR-4739的靶基因及启动子活性。Masson染色法检测胸膜纤维化程度，原位杂交法检测miR-4739的表达。过度调节miR-4739介导的间皮-间充质转化和增加PMC中胶原-I的合成对临床标本的研究显示，高水平的miR-4739和低水平的骨形态发生蛋白7（BMP-7）与患者的胸膜纤维化相关。然后我们接下来鉴定了miR-4739靶向并下调BMP-7，这进一步导致Smad 1/5/9和Smad 2/3信号转导之间的失衡。最后，体内研究揭示miR-4739过表达诱导胸膜纤维化，并且外源性BMP-7预防小鼠胸膜纤维化。miR-4739/BMP-7轴是一个很有前途的治疗靶点。
BackgroundPleural fibrosis is defined as excessive depositions of matrix components that result in pleural tissue architecture destruction and dysfunction. In severe cases, the progression of pleural fibrosis leads to lung entrapment, resulting in dyspnea and respiratory failure. However, the mechanism of pleural fibrosis is poorly understood.MethodsmiR-4739 levels were detected by miRNA array and real-time PCR. Real-time PCR, western blotting and immunofluorescence were used to identify the expression profile of indicators related to fibrosis. Target gene of miR-4739 and promoter activity assay was measured by using dual-luciferase reporter assay system. In vivo, pleural fibrosis was evaluated by Masson staining and miR-4739 level was detected by In situ hybridization histochemistry.FindingsWe found that bleomycin induced up-regulation of miR-4739 in pleural mesothelial cells (PMCs). Over-regulated miR-4739 mediated mesothelial-mesenchymal transition and increased collagen-I synthesis in PMCs. Investigation on the clinical specimens revealed that high levels of miR-4739 and low levels of bone morphogenetic protein 7 (BMP-7) associated with pleural fibrosis in patients. Then we next identified that miR-4739 targeted and down-regulated BMP-7 which further resulted in unbalance between Smad1/5/9 and Smad2/3 signaling. Lastly, in vivo studies revealed that miR-4739 over-expression induced pleural fibrosis, and exogenous BMP-7 prevented pleural fibrosis in mice.InterpretationOur data indicated that miR-4739 targets BMP-7 which mediates pleural fibrosis. The miR-4739/BMP-7 axis is a promising therapeutic target for the disease.FundThe National Natural Science Foundation of China.