Loss of miR-200c expression induces an aggressive, invasive, and chemoresistant phenotype in non-small cell lung cancer

The development of metastases is the main reason for cancer-related death in non-small cell lung cancer (NSCLC). The initiation of metastasis involves an increase in cell motility mediated by the loss of cell-cell adhesion caused by E-cadherin repression, in a process commonly known as epithelial-to...

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Bibliographic Details
Published in:Molecular cancer research 2010-09, Vol.8 (9), p.1207-1216
Main Authors: Ceppi, Paolo, Mudduluru, Giridhar, Kumarswamy, Regalla, Rapa, Ida, Scagliotti, Giorgio V, Papotti, Mauro, Allgayer, Heike
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - pharmacology
Antibodies, Monoclonal, Humanized
Cadherins - metabolism
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - pathology
Cell Line, Tumor
Cetuximab
Chick Embryo
Cisplatin - pharmacology
DNA Methylation - drug effects
Drug Resistance, Neoplasm - drug effects
Drug Resistance, Neoplasm - genetics
Female
Gene Expression Regulation, Neoplastic - drug effects
Humans
Lung Neoplasms - genetics
Lung Neoplasms - pathology
Lymph Nodes - pathology
Male
Mesoderm - drug effects
Mesoderm - pathology
MicroRNAs - genetics
MicroRNAs - metabolism
Middle Aged
Neoplasm Invasiveness
Neoplasm Metastasis
Phenotype
Promoter Regions, Genetic - genetics
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Summary:The development of metastases is the main reason for cancer-related death in non-small cell lung cancer (NSCLC). The initiation of metastasis involves an increase in cell motility mediated by the loss of cell-cell adhesion caused by E-cadherin repression, in a process commonly known as epithelial-to-mesenchymal transition. A role for microRNA-200 family members in regulating epithelial-to-mesenchymal transition has recently been indicated but data about their expression in lung tumors is still unavailable. The present study investigated the expression of miR-200c in a panel of NSCLC cell lines (n = 9), and a strong inverse correlation with invasion was detected. Reintroduction of miR-200c into highly invasive/aggressive NSCLC cells induced a loss of the mesenchymal phenotype by restoring E-cadherin and reducing N-cadherin expression, and inhibited in vitro cell invasion as well as in vivo metastasis formation. Moreover, miR-200c overexpression restored the sensitivity of NCI-H1299 cells to cisplatin and cetuximab. Hypermethylation of the promoter region was found to be responsible for the loss of miR-200c in invasive cells, as evaluated by 5-aza-2'-deoxycytidine treatment, methylation-specific PCR, and bisulfite sequencing. In primary tumor specimens obtained from 69 patients with consecutively resected NSCLC, lower miR-200c expression levels were found to be associated with a poor grade of differentiation (P = 0.04), a higher propensity to lymph node metastases (P < 0.01), and with a lower E-cadherin expression (P = 0.01). These data indicate that the loss of miR-200c expression induces an aggressive, invasive, and chemoresistant phenotype, and that assessment of its expression could contribute to a better clinicopathologic definition of patients with NSCLC.
ISSN:1541-7786
1557-3125
DOI:10.1158/1541-7786.mcr-10-0052