MicroRNA-19b Mediates Lung Epithelial-Mesenchymal Transition via Phosphatidylinositol-3,4,5-Trisphosphate 3-Phosphatase in Response to Mechanical Stretch
MicroRNA-19b Mediates Lung Epithelial-Mesenchymal Transition via Phosphatidylinositol-3,4,5-Trisphosphate 3-Phosphatase in Response to Mechanical Stretch
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微小RNA - 19b通过磷脂酰肌醇 - 3,4,5 - 三磷酸3 - 磷酸酶响应机械牵张介导肺上皮 - 间充质转化
DOI：
10.1165/rcmb.2015-0377oc
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发表时间：
2017-01-01
影响因子：
6.4
通讯作者：
Li, Yimin
中科院分区：
文献类型：
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作者：
Mao, Pu;Li, Jianchun;Li, Yimin
肺上皮间质转化（EMT）在呼吸机相关性肺纤维化中起重要作用，可能导致急性呼吸窘迫综合征患者预后不良。由于microRNA控制和调节正常的生理和病理生理过程，我们研究了microRNA在急性呼吸窘迫综合征相关EMT的发展中的作用，以响应机械应力。在目前的研究中，原代人肺泡上皮II型（AEII）细胞进行周期性拉伸，导致EMT的细胞角蛋白-8，E-cadherin和表面活性蛋白B的基因表达减少，波形蛋白，α-平滑肌肌动蛋白和N-钙粘蛋白的表达增加。微阵列分析显示microRNA-19 b（miR-19 b）在AEII细胞中表达上调，实时聚合酶链反应显示miR-19 b在AEII细胞和原代人小气道上皮细胞中表达增加。miR-19 b在小气道上皮细胞中的过表达促进了机械牵张诱导的EMT表型，而miR-19 b的抑制则减弱了这种表型，miR-19 b的抑制作用归因于增强了磷脂酰肌醇-3，4，5-三磷酸-3-磷酸酶（PTEN）的信号传导，导致AKT通路失活。PTEN表达的恢复或AKT磷酸化的抑制抑制了机械牵张诱导的EMT表型。我们进一步证明了机械牵张诱导的miR 19表达受粘着斑激酶-Rho通路的调节。总之，我们发现miR-19 b通过下调人肺上皮细胞中的PTEN以响应机械拉伸，在EMT表型的发展中起关键作用。miR-19 b-PTEN信号通路可能成为呼吸机相关肺纤维化的新治疗靶点。
Lung epithelial-mesenchymal transition (EMT) plays an important role in ventilation-associated lung fibrosis, which may contribute to the poor outcome of patients with acute respiratory distress syndrome. Because microRNAs control and modulate normal physiological and pathophysiological processes, we investigated the role of microRNAs in the development of acute respiratory distress syndrome-associated EMT in response to mechanical stress. In the current study, primary human alveolar epithelial type II (AEII) cells were subjected to cyclic stretch that resulted in EMT profiles with decreased gene expression of cytokeratin-8, E-cadherin, and surfactant protein B, and increased expression of vimentin, alpha-smooth muscle actin, and N-cadherin. Microarray analysis revealed that the expression of microRNA-19b (miR-19b) was up-regulated in the AEII cells, and real-time polymerase chain reaction showed that the expression of miR-19b increased in both the AEII cells and the primary human small-airway epithelial cells. Overexpression of miR-19b in small-airway epithelial cells promoted the mechanical stretch-induced EMT phenotypes, whereas inhibition of miR-19b attenuated it. The inhibitory effect of miR-19b was attributed to enhanced signaling of phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (PTEN), leading to inactivation of the AKT pathway. Restoration of PTEN expression or inhibition of AKT phosphorylation suppressed the mechanical stretch-induced EMT phenotypes. We further demonstrated that the mechanical stretch-induced miR19 expression was regulated by the focal adhesion kinase-Rho pathway. In conclusion, we found that miR-19b plays a key role in the development of the EMT phenotype through down-regulation of PTEN in human lung epithelial cells in response to mechanical stretch. The miR-19b-PTEN signaling pathway may serve as a novel therapeutic target in the context of ventilator-associated lung fibrosis.