Abstract
BackgroundTranslationally 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.MethodsTo 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.ResultsTranslationally 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.ConclusionsOur 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.
Highlights
Controlled tumor protein (TCTP) is linked to lung cancer
The present study aimed to investigate the role of Translationally controlled tumor protein (TCTP) in NNK/PM2.5-induced epithe‐ lial–mesenchymal transition (EMT) and how TCTP expression was regulated during this process
TCTP expression was related to PM2.5 and NNK induced EMT As shown in Fig. 1a, b, TCTP expression was up-regulated accompanied with cells exhibiting scattered, elongated, and mesenchymal-like morphology under PM2.5/ NNK treatment
Summary
Upon lung cancer carcinogens stimulation, there were no reports on the relationship between TCTP and lung cell carcinogenic epithe‐ lial–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. Among the numerous carcinogenic agents in tobacco products, 4-methylnitrosamino-l3-pyridyl-butanone (NNK) was a major contributor to non-small cell lung cancer (NSCLC) cell carcinogenesis and the molecular mechanism involved has been well studied [2]. Among the factors that contributed to the development of lung cancer in never smokers (LCNS), polluted air, especially particulate matter 2.5 (PM2.5), played the main role in lung carcinogenesis [3,4,5]. The phenotypic changes that characterized the transition from CSCs to differentiated cancer cells involved a process occurring in EMT [11]. EMT played a central role in the development of lung cancer [11]
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