title: Regulation of myofibroblast differentiation by miR-424 during epithelial-to-mesenchymal transition.
abstract: Idiopathic pulmonary fibrosis (IPF) is one of the most common and severe interstitial lung diseases. Epithelial-to-mesenchymal transition (EMT) is a process whereby epithelial cells undergo transition to a mesenchymal phenotype. This process has been shown to contribute to IPF. MicroRNAs (miRNAs) are small non-coding RNAs of 18-24 nucleotides in length which regulate gene expression. Several studies have implicated miRNAs in EMT; however, specific miRNAs that regulate EMT in IPF have not yet been identified. In this study, we identified 6 up-regulated and 3 down-regulated miRNAs in a human lung epithelial cell EMT model using miRNA microarray and real-time PCR. Overexpression of one of these up-regulated miRNAs, miR-424, increased the expression of α-smooth muscle actin, an indicator of myofibroblast differentiation, but had no effects on the epithelial or mesenchymal cell markers. miR-424 enhanced the activity of the TGF-β signaling pathway, as demonstrated by a luciferase reporter assay. Further experiments showed that miR-424 decreased the protein expression of Smurf2, a negative regulator of TGF-β signaling, indicating that miR-424 exerts a forward regulatory loop in the TGF-β signaling pathway. Our results suggest that miR-424 regulates the myofibroblast differentiation during EMT by potentiating the TGF-β signaling pathway, likely through Smurf2.
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: Chaoqun
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078, USA; Department of Physiology, Luzhou Medical College, Luzhou, Sichuan, People's Republic of China.
authors.forename: Chunling
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: Xuxu
authors.initials: X
authors.lastname: Gou
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: Lakmini K
authors.initials: LK
authors.lastname: Senavirathna
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: Myron
authors.initials: M
authors.lastname: Hinsdale
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Lloyd
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078, USA. Electronic address: lin.liu@okstate.edu.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D046228:Microarray Analysis; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D015415:Biomarkers; C554214:MIRN424 microrna, human; D035683:MicroRNAs; D053773:Transforming Growth Factor beta1; D008156:Luciferases; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Epithelial-to-mesenchymal transition; Idiopathic pulmonary fibrosis; Myofibroblast differentiation; Smurf2; TGF-β; miR-424