N-Cadherin Expression Is Associated with Acquisition of EMT Phenotype and with Enhanced Invasion in Erlotinib-Resistant Lung Cancer Cell Lines

The epidermal growth-factor receptor tyrosine kinase inhibitors have been effective in non-small cell lung cancer patients. However, acquired resistance eventually develops in most patients despite an initial positive response. Emerging evidence suggests that there is a molecular connection between...

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Published in:	PloS one Vol. 8; no. 3; p. e57692
Main Authors:	Zhang, Xiaoju, Liu, Guangzhi, Kang, Yi, Dong, Zhaogang, Qian, Qiyu, Ma, Xitao
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 08.03.2013 Public Library of Science (PLoS)
Subjects:	Adenocarcinoma Adenocarcinoma - drug therapy Adenocarcinoma - metabolism Adenocarcinoma - pathology Adult Aged Analysis Antigens, CD - biosynthesis Biology Biotechnology Cadherins - biosynthesis Cancer Cancer metastasis Cancer therapies Cell adhesion & migration Cell growth Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects Chemotherapy Drug Resistance, Neoplasm - drug effects E-cadherin Epidermal growth factor Epidermal growth factor receptors Epithelial-Mesenchymal Transition - drug effects Erlotinib Hydrochloride Female Flow cytometry Gene Expression Regulation, Neoplastic - drug effects Genetic aspects Genotype & phenotype Humans Inhibitor drugs Kinases Laboratories Lung cancer Lung diseases Lung Neoplasms - drug therapy Lung Neoplasms - metabolism Lung Neoplasms - pathology Male Medical prognosis Medicine Mesenchyme Metastases Metastasis Middle Aged N-Cadherin Neoplasm Invasiveness Neoplasm Proteins - biosynthesis Non-small cell lung cancer Non-small cell lung carcinoma Patients Prostate cancer Protein Kinase Inhibitors - administration & dosage Protein-tyrosine kinase receptors Quinazolines - administration & dosage Signal transduction siRNA Targeted cancer therapy Tissues Tumor cell lines Tyrosine Up-Regulation - drug effects Vimentin Western blotting China
ISSN:	1932-6203, 1932-6203
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Summary:	The epidermal growth-factor receptor tyrosine kinase inhibitors have been effective in non-small cell lung cancer patients. However, acquired resistance eventually develops in most patients despite an initial positive response. Emerging evidence suggests that there is a molecular connection between acquired resistance and the epithelial-mesenchymal transition (EMT). N-cadherin is involved in the EMT and in the metastasis of cancer cells. Here, we analyzed N-cadherin expression and function in erlotinib-resistant lung cancer cell lines. H1650 cell lines were used to establish the subline resistant to erlotinib(H1650ER). Then, induction of the EMT was analyzed using immunostaining and western blots in H1650ER cells. N-cadherin expression in the resistant cells was examined using FACS and western blot. In addition, an invasion assay was performed to characterize the resistant cells. The effects of N-cadherin on cell proliferation and invasion were analyzed. The association of N-cadherin expression with the EMT phenotype was investigated using immunohistochemical analysis of 13 archived, lung adenocarcinoma tissues, before and after treatment with erlotinib. In H1650ER cells, N-cadherin expression was upregulated, paralleled by the reduced expression of E-cadherin. The marked histological change and the development of a spindle-like morphology suggest that H1650ER cells underwent an EMT, accompanied by a decrease in E-cadherin and an increase in vimentin. A change in the EMT status between pre-and post-treatment was observed in 11 out of 13 cases (79%). In biopsies of resistant cancers, N-cadherin expression was increased in 10 out of 13 cases. Induction of the EMT was consistent with aggressive characteristics. Inhibition of N-cadherin expression by siRNA was tested to reduce proliferation and invasion of H1650ER cells in vitro. Our data provide evidence that induction of the EMT contributes to the acquired resistance to EGFR-TKIs in lung cancer. It suggests that N-cadherin is a potential molecular target in the treatment of NSCLC.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Feature-1 content type line 23 Conceived and designed the experiments: XJZ. Performed the experiments: XJZ ZGD QYQ. Analyzed the data: XJZ ZGD. Contributed reagents/materials/analysis tools: XJZ GZL YK. Wrote the paper: XJZ XTM. Competing Interests: The authors have declared that no competing interests exist.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0057692