High mobility group box 1-induced epithelial mesenchymal transition in human airway epithelial cells

作者：Chen Yu Ching; Statt Sarah; Wu Reen; Chang Hao Teng; Liao Jiunn Wang; Wang Chien Neng; Shyu Woei Cherng; Lee Chen Chen

来源：Scientific Reports, 2016, 6(1): 18815.

DOI：10.1038/srep18815

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 SK3 beta inactivation, cytoplasmic accumulation, and nuclear translocation of beta-catenin to induce EMT in human airway epithelial cells. Treatment with PI3K inhibitor (LY294006) and beta-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/GSK3 beta/beta-catenin signaling pathway.

• 出版日期2016-1-7
• 单位中国医科大学