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甘草酸通过TGF-β1/Smad2/3信号通路抑制高迁移率族蛋白盒1,从而抑制肺上皮细胞的上皮-间质转化。

Glycyrrhizin suppresses epithelial-mesenchymal transition by inhibiting high-mobility group box1 via the TGF-1/Smad2/3 pathway in lung epithelial cells.

作者信息

Gui Yanni, Sun Jian, You Wenjie, Wei Yuanhui, Tian Han, Jiang Shujuan

机构信息

Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.

Cheeloo Collage of Medicine, Shandong University, Jinan, Shandong, China.

出版信息

PeerJ. 2020 Feb 3;8:e8514. doi: 10.7717/peerj.8514. eCollection 2020.

Abstract

BACKGROUND

Epithelial-mesenchymal transition (EMT) plays an important role in fibrosis, chronic inflammation, tumor metastasis, etc. Glycyrrhizin, an active component extracted from licorice plant, has been reported to treat a variety of inflammatory reactions through inhibiting high-mobility group box1 (HMGB1), which has been suggested to be a significant mediator in EMT process. However, whether glycyrrhizin affects the EMT process or not remains unclear.

METHODS

Human alveolar epithelial cell line A549 and normal human bronchial epithelial cell line BEAS-2B were treated with extrinsic TGF-1 to induce EMT. Elisa was used to detect HMGB1 concentrations in cell supernatant. RNA interference and lentivirus infection experiments were performed to investigate the involvement of HMGB1 in EMT process. Cell Counting Kit-8 (CCK-8) was used to detect the viability of A549 and BEAS-2B cells treated with glycyrrhizin. Finally, the effects of glycyrrhizin on EMT changes, as well as the underlying mechanisms, were evaluated via Western blot, immunofluorescence and transwell assays.

RESULTS

Our results showed that HMGB1 expression was increased by TGF-1, and knockdown of HMGB1 expression reversed TGF-1-induced EMT in A549 and BEAS-2B cells. Ectopic HMGB1 expression or TGF-1 treatment caused a significant increase in HMGB1 release. Notably, we found that glycyrrhizin treatment effectively suppressed TGF-1-induced EMT process by inhibiting HMGB1. Also, glycyrrhizin significantly inhibited the migration of both A549 and BEAS-2B cells promoted by TGF-1. Mechanistically, HMGB1 overexpression could activate Smad2/3 signaling in A549 and BEAS-2B cells. Glycyrrhizin significantly blocked the phosphorylation of Smad2/3 stimulated either by TGF-1 or by ectopic HMGB1 in A549 and BEAS-2B cells.

CONCLUSIONS

HMGB1 is a vital mediator of EMT changes induced by TGF-1 in lung epithelial cells. Importantly, glycyrrhizin can effectively block Smad2/3 signaling pathway through inhibiting HMGB1, thereby suppressing the EMT progress.

摘要

背景

上皮-间质转化(EMT)在纤维化、慢性炎症、肿瘤转移等过程中发挥重要作用。甘草甜素是从甘草植物中提取的一种活性成分,据报道其可通过抑制高迁移率族蛋白B1(HMGB1)来治疗多种炎症反应,而HMGB1被认为是EMT过程中的一种重要介质。然而,甘草甜素是否影响EMT过程仍不清楚。

方法

用外源性转化生长因子-β1(TGF-β1)处理人肺泡上皮细胞系A549和正常人支气管上皮细胞系BEAS-2B以诱导EMT。采用酶联免疫吸附测定(ELISA)检测细胞上清液中HMGB1的浓度。进行RNA干扰和慢病毒感染实验以研究HMGB1在EMT过程中的作用。使用细胞计数试剂盒-8(CCK-8)检测经甘草甜素处理的A549和BEAS-2B细胞的活力。最后,通过蛋白质免疫印迹法、免疫荧光法和Transwell实验评估甘草甜素对EMT变化及其潜在机制的影响。

结果

我们的结果表明,TGF-β1可增加HMGB1的表达,而敲低HMGB1的表达可逆转TGF-β1诱导的A549和BEAS-2B细胞的EMT。异位表达HMGB1或用TGF-β1处理会导致HMGB1释放显著增加。值得注意的是,我们发现甘草甜素处理可通过抑制HMGB1有效抑制TGF-β1诱导的EMT过程。此外,甘草甜素显著抑制了TGF-β1促进的A549和BEAS-2B细胞的迁移。机制上,HMGB1过表达可激活A549和BEAS-2B细胞中的Smad2/3信号通路。甘草甜素可显著阻断TGF-β1或异位HMGB1刺激的A549和BEAS-2B细胞中Smad2/3的磷酸化。

结论

HMGB1是TGF-β1诱导的肺上皮细胞EMT变化的重要介质。重要的是,甘草甜素可通过抑制HMGB1有效阻断Smad2/3信号通路,从而抑制EMT进程。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4b7/7003690/a8dca018302d/peerj-08-8514-g001.jpg

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