title: Induction of a mesenchymal expression program in lung epithelial cells by wingless protein (Wnt)/β-catenin requires the presence of c-Jun N-terminal kinase-1 (JNK1).
abstract: Recent studies suggest the importance of the transition of airway epithelial cells (EMT) in pulmonary fibrosis, and also indicate a role for Wingless protein (Wnt)/β-catenin signaling in idiopathic pulmonary fibrosis. We investigated the possible role of the Wnt signaling pathway in inducing EMT in lung epithelial cells, and sought to unravel the role of c-Jun-N-terminal-kinase-1 (JNK1). The exposure of C10 lung epithelial cells or primary mouse tracheal epithelial cells (MTECs) to Wnt3a resulted in increases in JNK phosphorylation and nuclear β-catenin content. Because the role of β-catenin as a transcriptional coactivator is well established, we investigated T-cell factor/lymphocyte-enhancement factor (TCF/LEF) transcriptional activity in C10 lung epithelial cells after the activation of Wnt. TCF/LEF transcriptional activity was enhanced after the activation of Wnt, and this increase in TCF/LEF transcriptional activity was diminished after the small interfering (si)RNA-mediated ablation of JNK. The activation of the Wnt pathway by Wnt3a, or the expression of either wild-type or constitutively active β-catenin (S37A), led to the activation of an EMT transcriptome, manifested by the increased mRNA expression of CArG box-binding factor-A, fibroblast-specific protein (FSP)-1, α-smooth muscle actin (α-SMA), and vimentin, increases in the content of α-SMA and FSP1, and the concomitant loss of zona occludens-1. The siRNA-mediated ablation of β-catenin substantially decreased Wnt3a-induced EMT. The siRNA ablation of JNK1 largely abolished Wnt3a, β-catenin, and β-catenin S37a-induced EMT. In MTECs lacking Jnk1, Wnt3a-induced increases in nuclear β-catenin, EMT transcriptome, and the content of α-SMA or FSP1 were substantially diminished. These data show that the activation of the Wnt signaling pathway is capable of inducing an EMT program in lung epithelial cells through β-catenin, and that this process is controlled by JNK1.
authors.affiliation: Department of Pathology, Health Sciences Research Facility, Room 216A, University of Vermont, Burlington, VT 05405, USA. Yvonne.janssen@uvm.edu
authors.forename: Jos L J
authors.initials: JL
authors.lastname: van der Velden
authors.forename: Amy S
authors.initials: AS
authors.lastname: Guala
authors.forename: Susan E
authors.initials: SE
authors.lastname: Leggett
authors.forename: Jasper
authors.initials: J
authors.lastname: Sluimer
authors.forename: Elsbeth C H L
authors.initials: EC
authors.lastname: Badura
authors.forename: Yvonne M W
authors.initials: YM
authors.lastname: Janssen-Heininger
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D017931:DNA Primers; D004847:Epithelial Cells / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
chemical_list: D017931:DNA Primers; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin; D048055:Mitogen-Activated Protein Kinase 8