The permissive role of TCTP in PM2.5/NNK-induced epithelial–mesenchymal transition in lung cells

Abstract

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 (PM 2.5 ) or 4-methylnitrosamino-l-3-pyridyl-butanone (NNK)]-induced EMT, PM 2.5 /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 PM 2.5 /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, PM 2.5 /NNK stimulation brought a synergistic effect on EMT in TCTP-transfected cells. TCTP knockdown blocked PM 2.5 /NNK carcinogenic effect. Mechanically, PM 2.5 /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 PM 2.5 /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.© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article' s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article'

Dysregulation of TCTP in Biological Processes and Diseases

“…Using the same cell line, it was further confirmed that TCTP promotes EMT and tumorigenicity [90,91] by influencing the expression levels of key transcription factors (ZEB1 and alpha SMA), and of miR-200a, miR-141, and miR-424 [90]. A very recent study also showed that TCTP is a key mediator in the induction of EMT by cigarette smoke carcinogens in lung epithelial and non-small-cell lung cancer cells [70]. Overall, these recent reports on the essential role of TCTP in EMT generated substantial support for our original observation [77] that decreased cellular levels of TCTP in cancer cells inhibit tumorigenicity by interfering with migration and invasion.…”

“…In the latter case, the authors observed that miR-27b levels were significantly reduced in tumor tissue of oral cancer patients, resulting in an increase of TCTP protein expression. Similarly, two recent papers reported on the deregulated TCTP expression in cancer, due to low levels of certain miRNAs, i.e., miR-145-5p in prolactinoma [69] and miR-125-3p in lung cancer [70]. In the latter paper, the authors studied the induction of TCTP in lung cells by tobacco smoke carcinogens.…”

Targeting CD36 determines nicotine derivative NNK-induced lung adenocarcinoma carcinogenesis

“…And more, NNK and its metabolites in the lung cell could activate some targets, such as TCTP, 15-LOXs PPARγ, and HO-1, to promote lung cell carcinogenesis. 25 , 26 , 31 , 35 Obviously, the signaling events induced by NNK through α7nAChR-CD36 have a significant contribution to the carcinogenic process.…”

“…IHC was performed according to the procedure of ABC-HRP kit (Vector Laboratories, Burlinegame, CA) and protein expression levels were scored 1 to 12 according to the IRS method. 35 , 51 The immunoreactive score (IRS) was calculated as intensity of the staining reaction multiplied by the percentage of positive cells. IF was performed as described previously.…”

The activated CD36-Src axis promotes lung adenocarcinoma cell proliferation and actin remodeling-involved metastasis in high-fat environment

“…Vimentin antibody (46173) was purchased from Cell Signaling (Boston, MA). Protein expression levels were scored as previous description [ 51 , 52 ]. 5 μm paraffin sections of the tissues were stained with haematoxylin-eosin for 3–5 min.…”