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Cancer Chemotherapy and Pharmacology

Published in:

01-12-2018 | Original Article

FOXC2 promotes epithelial–mesenchymal transition and cisplatin resistance of non-small cell lung cancer cells

Authors: Yuwen He, Hui Xie, Pengjiu Yu, Shunjun Jiang, Li Wei

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2018

Abstract

Purpose

Platinum-based drugs, particularly cisplatin (DDP), are used in the treatment of non-small cell lung cancer (NSCLC). However, development of drug resistance remains the major therapeutic barrier in NSCLC.

Methods

The potential cisplatin resistance-related genes were identified from the global transcriptomes of cisplatin-resistant A549/DDP cells using microarray analysis. Gain- and loss-of-function assays were performed to analyze the effects of Forkhead Box Protein C2 (FOXC2) on the in vitro and in vivo sensitivity of NSCLC cells to cisplatin and its possible molecular mechanisms.

Results

Using global transcriptome analysis, we found that FOXC2 was one of the most upregulated molecules in A549/DDP cells compared with A549 cells. We further confirmed that the expression of FOXC2 was significantly increased in cisplatin-resistant NSCLC tissues. FOXC2 knockdown significantly increased the in vitro and in vivo sensitivity of A549/DDP cells to cisplatin, whereas overexpression of FOXC2 increased cisplatin resistance in cisplatin-sensitive NSCLC cells. Moreover, we found that FOXC2 promoted cisplatin resistance by induction of epithelial–mesenchymal transition (EMT) in NSCLC cells. Furthermore, FOXC2 activated the AKT/GSK3β signaling pathway, and then increased the protein expression of EMT-related transcription factor Snail. Inhibition of AKT or knockdown of Snail reversed FOXC2-induced EMT and cisplatin resistance of NSCLC cells.

Conclusion

FOXC2 enhanced cisplatin resistance of NSCLC cells through activating AKT/GSK3β/Snail/EMT signaling pathway, which may be a potential novel therapeutic target for overcoming drug resistance in human NSCLCs.

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Title: FOXC2 promotes epithelial–mesenchymal transition and cisplatin resistance of non-small cell lung cancer cells
Authors: Yuwen He
Hui Xie
Pengjiu Yu
Shunjun Jiang
Li Wei
Publication date: 01-12-2018
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 6/2018
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-018-3697-2

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