title: High mobility group box 1-induced epithelial mesenchymal transition in human airway epithelial cells.
abstract: Epithelial-mesenchymal transition (EMT) is implicated in bronchial remodeling and loss of lung function in chronic inflammatory airway diseases. Previous studies showed the involvement of the high mobility group box 1 (HMGB1) protein in the pathology of chronic pulmonary inflammatory diseases. However, the role of HMGB1 in EMT of human airway epithelial cells is still unclear. In this study, we used RNA sequencing to show that HMGB1 treatment regulated EMT-related gene expression in human primary-airway epithelial cells. The top five upregulated genes were SNAI2, FGFBP1, VIM, SPARC (osteonectin), and SERPINE1, while the downregulated genes included OCLN, TJP1 (ZO-1), FZD7, CDH1 (E-cadherin), and LAMA5. We found that HMGB1 induced downregulation of E-cadherin and ZO-1, and upregulation of vimentin mRNA transcription and protein translation in a dose-dependent manner. Additionally, we observed that HMGB1 induced AKT phosphorylation, resulting in GSK3β inactivation, cytoplasmic accumulation, and nuclear translocation of β-catenin to induce EMT in human airway epithelial cells. Treatment with PI3K inhibitor (LY294006) and β-catenin shRNA reversed HMGB1-induced EMT. Moreover, HMGB1 induced expression of receptor for advanced glycation products (RAGE), but not that of Toll-like receptor (TLR) 2 or TLR4, and RAGE shRNA inhibited HMGB1-induced EMT in human airway epithelial cells. In conclusion, we found that HMGB1 induced EMT through RAGE and the PI3K/AKT/GSK3β/β-catenin signaling pathway.
authors.affiliation: Graduate Institute of Immunology, College of Medicine, China Medicine University, Taichung, Taiwan.
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Center for Comparative Respiratory Biology and Medicine, Internal Medicine, College of Medicine, University of California at Davis, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Statt
authors.affiliation: Center for Comparative Respiratory Biology and Medicine, Internal Medicine, College of Medicine, University of California at Davis, USA.
authors.forename: Reen
authors.initials: R
authors.lastname: Wu
authors.affiliation: Institute of Basic Medical Science, College of Medicine, China Medicine University, Taichung, Taiwan.
authors.forename: Hao-Teng
authors.initials: HT
authors.lastname: Chang
authors.affiliation: Institute of Veterinary Pathology, College of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Jiunn-Wang
authors.initials: JW
authors.lastname: Liao
authors.affiliation: Institute of Basic Medical Science, College of Medicine, China Medicine University, Taichung, Taiwan.
authors.forename: Chien-Neng
authors.initials: CN
authors.lastname: Wang
authors.affiliation: Graduate Institute of Immunology, College of Medicine, China Medicine University, Taichung, Taiwan.
authors.forename: Woei-Cherng
authors.initials: WC
authors.lastname: Shyu
authors.affiliation: Graduate Institute of Immunology, College of Medicine, China Medicine University, Taichung, Taiwan.|Institute of Basic Medical Science, College of Medicine, China Medicine University, Taichung, Taiwan.|Department of Microbiology and Immunology, School of Medicine, China Medicine University, Taichung, Taiwan.|Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Chen-Chen
authors.initials: CC
authors.lastname: Lee
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D004847:Epithelial Cells / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition; D015870:Gene Expression; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D024243:HMGB1 Protein / Q000502:physiology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; C495270:CTNNB1 protein, human; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; C498978:MOK protein, human; D020928:Mitogen-Activated Protein Kinases