The permissive role of TCTP in PM2.5/NNK-induced epithelial-mesenchymal transition in lung cells
The permissive role of TCTP in PM2.5/NNK-induced epithelial-mesenchymal transition in lung cells
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TCTP在PM2.5/NNK诱导的肺细胞上皮间质转化中的许可作用
DOI：
10.1186/s12967-020-02256-5
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发表时间：
2020-02-11
影响因子：
7.4
通讯作者：
Li, Ming-Yue
中科院分区：
文献类型：
--
作者：
Liu, Li-Zhong;Wang, Menghuan;Li, Ming-Yue
背景翻译控制肿瘤蛋白（TCTP）与肺癌有关。然而，在肺癌致癌物刺激下，TCTP与肺细胞致癌性上皮间质转化（EMT）的关系尚未见报道。本研究旨在探讨TCTP表达调控的分子机制及其在肺癌诱导EMT中的作用。方法采用肺上皮细胞和非小细胞肺癌（NSCLC）细胞，研究TCTP在肺致癌物PM2.5或4-甲基亚硝胺基-1-3-吡啶丁酮（NNK）诱导EMT中的作用。细胞来源的异种移植物、人肺癌样品和在线存活分析用于确认结果。通过MassArray、Real-time PCR和Reporter等方法研究TCTP的表达调控机制。所有统计分析均使用GraphPad Prism 6.0版或SPSS 20.0版进行。结果PM2.5/NNK处理的肺细胞和原位种植瘤中翻译控制的肿瘤蛋白和波形蛋白表达上调。TCTP表达与波形蛋白在人NSCLC样品中呈正相关。TCTP高表达的患者的总体生存期和无病生存期较低。TCTP过表达可增加波形蛋白表达并促进细胞转移。此外，PM2.5/NNK刺激在TCTP转染的细胞中对EMT产生协同效应。TCTP敲低阻断PM2.5/NNK致癌作用。PM2.5/NNK诱导的TCTP表达受一种microRNA调控，即miR-125 a-3 p，而不受TCTP基因启动子甲基化的调控。在PM2. 5/NNK刺激过程中，TCTP的表达水平受其特异性microRNA的调控，从而促进波形蛋白的表达，在致癌性EMT中发挥允许作用。结论TCTP在肺癌诱导EMT中的表达调控机制为进一步研究提供了新的思路。TCTP和miR-125 a-3 p可能是NSCLC潜在的预后生物标志物和治疗靶点。
Background Translationally controlled tumor protein (TCTP) is linked to lung cancer. However, upon lung cancer carcinogens stimulation, there were no reports on the relationship between TCTP and lung cell carcinogenic epithelial-mesenchymal transition (EMT). This study was designed to investigate the molecular mechanism of regulation of TCTP expression and its role in lung carcinogens-induced EMT. Methods To study the role of TCTP in lung carcinogens [particulate matter 2.5 (PM2.5) or 4-methylnitrosamino-l-3-pyridyl-butanone (NNK)]-induced EMT, PM2.5/NNK-treated lung epithelial and non-small cell lung cancer (NSCLC) cells were tested. Cell derived xenografts, human lung cancer samples and online survival analysis were used to confirm the results. MassArray assay, Real-time PCR and Reporter assays were performed to elucidate the mechanism of regulation of TCTP expression. All statistical analyses were performed using GraphPad Prism version 6.0 or SPSS version 20.0. Results Translationally controlled tumor protein and vimentin expression were up-regulated in PM2.5/NNK-treated lung cells and orthotopic implantation tumors. TCTP expression was positively correlated with vimentin in human NSCLC samples. Patients with high expression of TCTP displayed reduced overall and disease-free survival. TCTP overexpression could increase vimentin expression and promote cell metastasis. Furthermore, PM2.5/NNK stimulation brought a synergistic effect on EMT in TCTP-transfected cells. TCTP knockdown blocked PM2.5/NNK carcinogenic effect. Mechanically, PM2.5/NNK-induced TCTP expression was regulated by one microRNA, namely miR-125a-3p, but not by methylation on TCTP gene promoter. The level of TCTP was regulated by its specific microRNA during the process of PM2.5/NNK stimulation, which in turn enhanced vimentin expression and played a permissive role in carcinogenic EMT. Conclusions Our results provided new insights into the mechanisms of TCTP regulatory expression in lung carcinogens-induced EMT. TCTP and miR-125a-3p might act as potential prognostic biomarkers and therapeutic targets for NSCLC.