High mobility group box 1-induced epithelial mesenchymal transition in human airway epithelial cells.
High mobility group box 1-induced epithelial mesenchymal transition in human airway epithelial cells.
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DOI：
10.1038/srep18815
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发表时间：
2016-01-07
影响因子：
4.6
通讯作者：
Lee CC
中科院分区：
文献类型：
--
作者：
Chen YC;Statt S;Wu R;Chang HT;Liao JW;Wang CN;Shyu WC;Lee CC
上皮-间质转化（EMT）与慢性炎性气道疾病的支气管重塑和肺功能丧失有关。以往的研究表明，高迁移率组盒1 （HMGB1）蛋白参与了慢性肺部炎性疾病的病理过程。然而，HMGB1在人气道上皮细胞EMT中的作用尚不清楚。在本研究中，我们通过RNA测序显示HMGB1处理可调节人原代气道上皮细胞中emt相关基因的表达。上调最多的5个基因为SNAI2、FGFBP1、VIM、SPARC （osteonectin）和SERPINE1，下调最多的基因为OCLN、TJP1 （ZO-1）、FZD7、CDH1 （E-cadherin）和LAMA5。我们发现HMGB1诱导E-cadherin和ZO-1的下调，以及vimentin mRNA转录和蛋白翻译的上调呈剂量依赖性。此外，我们观察到HMGB1诱导AKT磷酸化，导致GSK3β失活、细胞质积累和β-catenin的核易位，从而诱导人气道上皮细胞的EMT。PI3K抑制剂（LY294006）和β-catenin shRNA治疗可逆转hmgb1诱导的EMT。此外，HMGB1诱导晚期糖基化产物受体（RAGE）的表达，而toll样受体（TLR） 2或TLR4的表达不受影响，RAGE shRNA抑制HMGB1诱导的人气道上皮细胞EMT。综上所述，我们发现HMGB1通过RAGE和PI3K/AKT/GSK3β/β-catenin信号通路诱导EMT。
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.