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

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

Research output: Contribution to journalArticle

309 Scopus citations

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 Iε (PKC-Iε) and sarcoma viral oncogene homolog (SRC). These findings suggest that modulation of specific miRNAs may provide a therapeutic approach for the treatment of NSCLCs.

Original languageEnglish (US)
Pages (from-to)74-82
Number of pages9
JournalNature Medicine
Volume18
Issue number1
DOIs
StatePublished - Jan 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Garofalo, M., Romano, G., Di Leva, G., Nuovo, G., Jeon, Y. J., Ngankeu, A., Sun, J., Lovat, F., Alder, H., Condorelli, G., Engelman, J. A., Ono, M., Rho, J. K., Cascione, L., Volinia, S., Nephew, K. P., & Croce, C. M. (2012). EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nature Medicine, 18(1), 74-82. https://doi.org/10.1038/nm.2577