title: MicroRNA-19b Mediates Lung Epithelial-Mesenchymal Transition via Phosphatidylinositol-3,4,5-Trisphosphate 3-Phosphatase in Response to Mechanical Stretch.
abstract: 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, α-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.
authors: 1 State Key Laboratory of Respiratory Diseases and Guangzhou Institute of Respiratory Diseases, Guangzhou, Guangdong, China.|2 The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors: Pu
authors: P
authors: Mao
authors: 1 State Key Laboratory of Respiratory Diseases and Guangzhou Institute of Respiratory Diseases, Guangzhou, Guangdong, China.|2 The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors: Jianchun
authors: J
authors: Li
authors: 1 State Key Laboratory of Respiratory Diseases and Guangzhou Institute of Respiratory Diseases, Guangzhou, Guangdong, China.|2 The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors: Yongbo
authors: Y
authors: Huang
authors: 1 State Key Laboratory of Respiratory Diseases and Guangzhou Institute of Respiratory Diseases, Guangzhou, Guangdong, China.|2 The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors: Songlin
authors: S
authors: Wu
authors: 1 State Key Laboratory of Respiratory Diseases and Guangzhou Institute of Respiratory Diseases, Guangzhou, Guangdong, China.|2 The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors: Xiaoqing
authors: X
authors: Pang
authors: 1 State Key Laboratory of Respiratory Diseases and Guangzhou Institute of Respiratory Diseases, Guangzhou, Guangdong, China.|2 The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors: Weiqun
authors: W
authors: He
authors: 1 State Key Laboratory of Respiratory Diseases and Guangzhou Institute of Respiratory Diseases, Guangzhou, Guangdong, China.|2 The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors: Xiaoqing
authors: X
authors: Liu
authors: 1 State Key Laboratory of Respiratory Diseases and Guangzhou Institute of Respiratory Diseases, Guangzhou, Guangdong, China.|2 The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.|3 The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada; and the.|Departments of 4 Medicine.
authors: Arthur S
authors: AS
authors: Slutsky
authors: 1 State Key Laboratory of Respiratory Diseases and Guangzhou Institute of Respiratory Diseases, Guangzhou, Guangdong, China.|2 The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.|Departments of 4 Medicine.|5 Anesthesia, and.|6 Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: Haibo
authors: H
authors: Zhang
authors: 1 State Key Laboratory of Respiratory Diseases and Guangzhou Institute of Respiratory Diseases, Guangzhou, Guangdong, China.|2 The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors: Yimin
authors: Y
authors: Li
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016366:Open Reading Frames / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: C549214:MIRN19A microRNA, human; D035683:MicroRNAs; D008156:Luciferases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; D020741:rho GTP-Binding Proteins
keywords: acute respiratory distress syndrome; epithelial-mesenchymal transition; microRNA; phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase; stretch