title: MiR-449a regulates autophagy to inhibit silica-induced pulmonary fibrosis through targeting Bcl2.
abstract: Silicosis is a fatal pulmonary fibrotic disorder characterized by accumulation of fibroblasts and myofibroblasts and deposition of extracellular matrix proteins. MiR-449a is a potential mediator of many cellular processes, including cell proliferation, differentiation, and apoptosis. We hypothesized that miR-449a may play a crucial role in the progression of pulmonary fibrogenesis. Here, we described miR-449a as a new autophagy-regulated miRNA. Importantly, miR-449a expression was significantly decreased in lung tissues of mice with silica treatment, and it was similarly expressed in NIH-3T3 and MRC-5 cells stimulated with TGF-β1. The activity of autophagy was inhibited in fibrotic lung tissues and TGF-β1-treated fibroblasts. To investigate the potential effect of miR-449a, we overexpressed miR-449a in mouse models and found that miR-449a significantly reduced both the distribution and severity of lung lesions induced by silica. In addition, miR-449a was observed to induce the activity of autophagy in vivo and in vitro. Notably, Bcl2 was identified as a target of miR-449a. Bcl2 levels were decreased in NIH-3T3 cells upon miR-449a overexpression. Indeed, the Bcl2 3' UTR contained functional miR-449a responsive sequences. Furthermore, TGF-β1 was observed to increase the expression of Bcl2 via the MAPK/ERK pathway. These results suggest that miR-449a is an important regulator of autophagy, as well as a novel endogenous suppressor of pulmonary fibrosis.
  
  
  
  MiR-449a expression was decreased in fibrotic lungs and activated fibroblasts. Autophagy was inhibited in fibrotic lung tissues and TGF-β1-treated fibroblasts. MiR-449a had an antifibrotic effect in silica-induced lung fibrosis. MiR-449a upregulated autophagic activity in vitro. Bcl2 is the autophagy-related target of miR-449a.
authors.affiliation: Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
authors.forename: Ruhui
authors.initials: R
authors.lastname: Han
authors.affiliation: Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Ji
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Rong
authors.affiliation: Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
authors.forename: Wenxi
authors.initials: W
authors.lastname: Yao
authors.affiliation: Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
authors.forename: Qiuyun
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
authors.forename: Jingjin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
authors.forename: Weiwen
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.|Institute of Occupational Disease Prevention, Jiangsu Provincial Center for Disease Prevention and Control, Nanjing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.affiliation: Institute of Occupational Disease Prevention, Jiangsu Provincial Center for Disease Prevention and Control, Nanjing, China.
authors.forename: Baoli
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China. chninjmu@126.com.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Ni
mesh_terms: D000818:Animals; D000071182:Autophagosomes / Q000378:metabolism / Q000648:ultrastructure; D001343:Autophagy / Q000235:genetics*; D001483:Base Sequence; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D041681:NIH 3T3 Cells; D059748:Proteolysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D012822:Silicon Dioxide; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D035683:MicroRNAs; C538721:Mirn449 microRNA, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D053773:Transforming Growth Factor beta1; D012822:Silicon Dioxide; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Autophagy; Bcl2; MiR-449a; Silicosis