EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers.
EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers.
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.
- OHIO STATE UNIVERSITY
- University of Ulsan Korea (Republic of)
- Harvard University United States
- Kyushu University Japan
- The Ohio State University United States
Male, Epithelial-Mesenchymal Transition, Lung Neoplasms, 610, Mice, Nude, Antineoplastic Agents, Apoptosis, Gefitinib, Proto-Oncogene Proteins c-met, Article, ErbB Receptors, Gene Expression Regulation, Neoplastic, Mice, MicroRNAs, Cell Transformation, Neoplastic, Drug Resistance, Neoplasm, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Quinazolines, Animals, Humans, Cell Proliferation
Male, Epithelial-Mesenchymal Transition, Lung Neoplasms, 610, Mice, Nude, Antineoplastic Agents, Apoptosis, Gefitinib, Proto-Oncogene Proteins c-met, Article, ErbB Receptors, Gene Expression Regulation, Neoplastic, Mice, MicroRNAs, Cell Transformation, Neoplastic, Drug Resistance, Neoplasm, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Quinazolines, Animals, Humans, Cell Proliferation
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