Tobacco smoke induced hepatic cancer stem cell-like properties through IL-33/p38 pathway
Tobacco smoke induced hepatic cancer stem cell-like properties through IL-33/p38 pathway
复制标题
烟草烟雾通过 IL-33/p38 途径诱导肝癌干细胞样特性。
DOI：
10.1186/s13046-019-1052-z
复制
发表时间：
2019-01-28
影响因子：
11.3
通讯作者：
Li, Xiaoting
中科院分区：
文献类型：
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作者：
Xie, Chunfeng;Zhu, Jianyun;Li, Xiaoting
烟草烟雾（TS）对肝细胞癌的发展至关重要。TS诱导的肿瘤干细胞是肿瘤发生的早期事件。包括炎症因子在内的肿瘤特异性微环境是通过各种途径如p38 MAPK维持CSC干细胞的关键介质。然而，在TS诱导的肝CSCs特性的获得中的炎症因子的机制仍然不确定。本研究的目的是研究IL-33/p38轴在长期TS诱导的小鼠肝组织和人肝细胞获得肝CSCs特性中的作用。通过免疫组化、免疫荧光和Western blot分析小鼠肝组织病理学、IL-33水平、肝CSCs标志物、EMT样改变和p38 MAPK活化的变化。此外，将LO 2永生化的人肝细胞暴露于香烟烟雾提取物（CSE），并测定肿瘤球形成能力。进一步用IL-33或CSE处理LO 2细胞，检测磷酸化p38、肝CSCs标志物和EMT相关蛋白的表达，长期TS暴露可增加CSCs标志物的水平，诱导上皮细胞向间质细胞转化（EMT）和炎症因子IL-33的表达。此外，我们表明，p38 MAPK调制TS刺激的肝CSC样的属性，证明了长期TS曝光激活p38，和TS诱导的干性被废除的p38抑制的研究结果。体外实验结果显示，IL-33与香烟烟雾提取物（CSE）相似，促进了p38的活化，增加了肝CSC标志物的表达水平，并导致了EMT样改变，提示IL-33/p38轴在TS长期刺激诱导肝CSC样特性的获得中起重要作用。
Tobacco smoke (TS) critically contributes to the development of hepatocellular carcinoma. Cancer stem cells (CSCs) induced by TS is an early event in the initiation of carcinogenesis. Tumor specific microenvironment including inflammatory factors is key mediator for maintaining the stemness of CSCs through various pathways such as p38 MAPK. However, the mechanisms of inflammatory factors in TS-induced acquisition of liver CSCs properties remain undefined. The aim of this study was to investigate the role of IL-33/p38 axis in long term TS-induced acquisition of hepatic CSCs properties in mouse liver tissues and human liver cells.BALB/c mice were exposed to TS for 12 weeks, along with or without 1 mg/kg SB203580 (p38 inhibitors) treatment. Histopathological analysis, alterations in the levels of IL-33, liver CSCs markers, EMT-like changes and p38 MAPK activation in liver tissues of mice were analyzed by immunohistochemical staining, immunofluorescence assay and Western blot analysis. Moreover, LO2 immortalized human liver cells were exposed to cigarette smoke extract (CSE) and the tumorsphere formation ability was determined. LO2 cells were further treated with IL-33 or CSE and the expression of phosphorylated p38, liver CSCs markers and EMT-related proteins was examined.Long term TS exposure increased the levels of CSCs markers, induced epithelial-to mesenchymal transition (EMT) and inflammatory factor IL-33 expression. Moreover, we showed that p38 MAPK modulated TS-stimulated hepatic CSC-like properties, as evidenced by the findings that long term TS exposure activated p38, and that TS-induced stemness was abolished by p38 inhibition. In addition, data from in vitro model showed that similar to cigarette smoke extract (CSE), IL-33 treatment promoted the activation of p38, increased the levels of liver CSCs markers expression and EMT-like changes.Collectively, these data suggested that IL-33/p38 axis plays an important role in long term TS exposure-induced acquisition of hepatic CSC-like properties.