Song Li, Guo Linlin, Li Zhuoyu
Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China.
Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China; College of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, China.
Toxicol Appl Pharmacol. 2017 May 1;322:75-88. doi: 10.1016/j.taap.2017.03.003. Epub 2017 Mar 8.
Polychlorinated biphenyls (PCBs) are classic persistent organic pollutants (POPs). Many studies have found a positive association between the progression of hepatocellular carcinoma (HCC) and PCBs exposure. However, the influence of PCBs on epithelial-mesenchymal transition (EMT) of HCC remains to be unclear. In this study, we explored the effect of PCB126 on EMT in HCC cells and its underlying mechanisms. The data showed that PCB126, exposing both Bel-7402 and SMMC-7721 cells for 48h, promoted EMT that was demonstrated by E-cadherin repression, up-regulation of N-cadherin and vimentin, and morphological alteration. We found that signal transducer and activator of transcription 3 (STAT3)/Snail1 signaling was activated after PCB126 exposure, and the addition of STAT3 inhibitor WP1066 blocked PCB126-induced down-regulation of E-cadherin as well as up-regulation of N-cadherin and vimentin. Moreover, PCB126 exposure increased pyruvate kinase M2 (PKM2) expression and its nuclear translocation, whereas treatment with PKM2 shRNA suppressed the activation of STAT3/Snail1 signaling and the alternation of EMT-related molecules (E-cadherin, N-cadherin and vimentin). Furthermore, this study indicated estrogen receptor (ER) and aryl hydrocarbon receptor (AhR) were involved in PCB126-induced effects on PKM2, STAT3/Snail1 signaling and EMT by according treatment using ER inhibitor ICI and AhR shRNA. Notably, PCB126-increased reactive oxygen species (ROS) production via AhR is associated with activation of PKM2/STAT3/Snail1 cascades and contributes to EMT. Taken together, these results indicated that PCB126 promotes EMT process of HCC cells via PKM2/STAT3/Snail1 signaling which is mediated by ER and AhR.
多氯联苯（PCBs）是典型的持久性有机污染物（POPs）。许多研究发现肝细胞癌（HCC）进展与多氯联苯暴露之间存在正相关。然而，多氯联苯对肝癌上皮-间质转化（EMT）的影响仍不清楚。在本研究中，我们探讨了多氯联苯126对肝癌细胞EMT的影响及其潜在机制。数据显示，多氯联苯126作用于Bel-7402和SMMC-7721细胞48小时后，促进了EMT，表现为E-钙黏蛋白表达受抑、N-钙黏蛋白和波形蛋白上调以及形态改变。我们发现多氯联苯126暴露后信号转导和转录激活因子3（STAT3）/Snail1信号被激活，添加STAT3抑制剂WP1066可阻断多氯联苯126诱导的E-钙黏蛋白下调以及N-钙黏蛋白和波形蛋白上调。此外，多氯联苯126暴露增加了丙酮酸激酶M2（PKM2）的表达及其核转位，而用PKM2 shRNA处理可抑制STAT3/Snail1信号的激活以及EMT相关分子（E-钙黏蛋白、N-钙黏蛋白和波形蛋白）的改变。此外，本研究表明雌激素受体（ER）和芳烃受体（AhR）通过使用ER抑制剂ICI和AhR shRNA的相应处理参与了多氯联苯126对PKM2、STAT3/Snail1信号和EMT的诱导作用。值得注意的是，多氯联苯126通过AhR增加活性氧（ROS）的产生与PKM2/STAT3/Snail1级联的激活有关，并促进了EMT。综上所述，这些结果表明多氯联苯126通过由ER和AhR介导的PKM2/STAT3/Snail1信号促进肝癌细胞的EMT过程。
