EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers.

Abstract

The involvement of the MET oncogene in de novo and acquired resistance of non-small cell lung cancers (NSCLCs) to tyrosine kinase inhibitors (TKIs) has previously been reported, but the precise mechanism by which MET overexpression contributes to TKI-resistant NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To understand their role in TKI-resistant NSCLCs, we examined changes in miRNA that are mediated by tyrosine kinase receptors. Here we report that miR-30b, miR-30c, miR-221 and miR-222 are modulated by both epidermal growth factor (EGF) and MET receptors, whereas miR-103 and miR-203 are controlled only by MET. We showed that these miRNAs have important roles in gefitinib-induced apoptosis and epithelial-mesenchymal transition of NSCLC cells in vitro and in vivo by inhibiting the expression of the genes encoding BCL2-like 11 (BIM), apoptotic peptidase activating factor 1 (APAF-1), protein kinase C ɛ (PKC-ɛ) and sarcoma viral oncogene homolog (SRC). These findings suggest that modulation of specific miRNAs may provide a therapeutic approach for the treatment of NSCLCs.

• Authors: Michela Garofalo, Giulia Romano, Gianpiero Di Leva, Gerard Nuovo, Young-Jun Jeon, Apollinaire Ngankeu, Jin Sun, Francesca Lovat, Hansjuerg Alder, Gerolama Condorelli, Jeffrey A Engelman, Mayumi Ono, Jin Kyung Rho, Luciano Cascione, Stefano Volinia, Kenneth P Nephew, Carlo M Croce
• Journal: Nature medicine (Nat Med) Vol. 18 Issue 1 Pg. 74-82 (Dec 11 2011) ISSN: 1546-170X [Electronic] United States
• PMID: 22157681 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Antineoplastic Agents
• MicroRNAs
• Quinazolines
• EGFR protein, human
• ErbB Receptors
• MET protein, human
• Proto-Oncogene Proteins c-met
• Gefitinib

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Cell Proliferation
• Cell Transformation, Neoplastic (genetics)
• Drug Resistance, Neoplasm (genetics)
• Epithelial-Mesenchymal Transition (drug effects)
• ErbB Receptors (antagonists & inhibitors, genetics)
• Gefitinib
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms (drug therapy, genetics, pathology)
• Male
• Mice
• Mice, Nude
• MicroRNAs (genetics)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, genetics)
• Quinazolines (therapeutic use)
• Signal Transduction