Journal
JOURNAL OF CELLULAR PHYSIOLOGY
Volume 234, Issue 6, Pages 8804-8814Publisher
WILEY
DOI: 10.1002/jcp.27540
Keywords
airway remodeling; asthma; epithelial-mesenchymal transition (EMT); microRNA-448-5p; Sine oculis homeobox homolog 1 (Six1)
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Funding
- National Natural Science Foundation of China [81700029]
- Natural Science Foundation of Shandong Province [ZR2017PH032, ZR2017MH017]
- Higher Educational Science and Technology Program of Shandong Province [J17B092]
- Qingdao Scientific and Technologic Development Program [16-6-2-15-nsh]
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MicroRNAs (miRNAs) are small yet versatile gene tuners that regulate a variety of cellular processes, including cell growth and proliferation. The aim of this study was to explore how miR-448-5p affects airway remodeling and transforming growth factor-beta 1 (TGF-beta 1)-stimulated epithelial-mesenchymal transition (EMT) by targeting Sine oculis homeobox homolog 1 (Six1) in asthma. Asthmatic mice models with airway remodeling were induced with ovalbumin solution. MiRNA expression was evaluated using quantitative real-time polymerase chain reaction. Transfection studies of bronchial epithelial cells were performed to determine the target genes. A luciferase reporter assay system was applied to identify whether Six1 is a target gene of miR-448-5p. In the current study, we found that miR-448-5p was dramatically decreased in lung tissues of asthmatic mice and TGF-beta 1-stimulated bronchial epithelial cells. In addition, the decreased level of miR-448-5p was closely associated with the increased expression of Six1. Overexpression of miR-448-5p decreased Six1 expression and, in turn, suppressed TGF-beta 1-mediated EMT and fibrosis. Next, we predicted that Six1 was a potential target gene of miR-448-5p and demonstrated that miR-448-5p could directly target Six1. An SiRNA targeting Six1 was sufficient to suppress TGF-beta 1-induced EMT and fibrosis in 16HBE cells. Furthermore, the overexpression of Six1 partially reversed the protective effect of miR-448-5p on TGF-beta 1-mediated EMT and fibrosis in bronchial epithelial cells. Taken together, the miR-448-5p/TGF-beta 1/Six1 link may play roles in the progression of EMT and pulmonary fibrosis in asthma.
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