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-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.
Ceppi
Paolo
P
Department of Clinical and Biological Sciences, University of Turin at San Luigi Hospital, Orbassano, Italy.
Mudduluru
Giridhar
G
Kumarswamy
Regalla
R
Rapa
Ida
I
Scagliotti
Giorgio V
GV
Papotti
Mauro
M
Allgayer
Heike
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D015820:Cadherins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D002642:Chick Embryo; D002945:Cisplatin / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015820:Cadherins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D000068818:Cetuximab; D002945:Cisplatin