Abstract
Abstract The development of metastasis is the main reason for cancer-related death in non-small cell lung cancer (NSCLC). 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 (EMT). A central role for microRNA-200 family members in regulating EMT has been recently indicated, but data regarding the significance of their expression in lung tumors are still unavailable. The present study investigated the expression of mir-200c in a panel of NSCLC cell lines (n=9) and found a strong inverse correlation with cell invasive potential. Forced re-introduction of mir-200c into highly invasive/aggressive NSCLC cells induced a loss of mesenchymal phenotype, by restoring E-cadherin and reducing N-cadherin expression, and inhibited in vitro cell invasion as well as in vivo metastasis formation, as evaluated by chicken embryo metastasis assay. Moreover, mir-200c overexpression restored the sensitivity towards cisplatin and cetuximab, two chemotherapeutic agents widely used in the treatments of thoracic cancers, of the drug-resistant NCI-H1299 cells. Hyper-methylation of the promoter region was found to be the mechanism behind the loss of mir-200c in invasive cells, as evaluated by 5-aza-dC treatment and methylation specific PCR. In primary tumor specimens obtained from 45 consecutively resected NSCLC patients, mir-200c expression confirmed its role in malignant tumor progression, being significantly inversely associated with a poor grade of differentiation (p=0.01) and a higher propensity to lymph node metastases (p<0.01). In conclusion, these data indicate that loss of miR-200c expression plays an important role in the initiation of an aggressive, invasive, and chemoresistant phenotype. The determination of its expression in tumors can be used for the stratification of the patients to be treated with anti-metastatic therapy. Citation Information: Clin Cancer Res 2010;16(7 Suppl):A24
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