MicroRNA-506-3p reverses gefitinib resistance in non-small cell lung cancer by targeting Yes-associated protein 1

Abstract

Epidermal growth factor receptor-tyrosine kinase inhibitors, such as gefitinib, have been found to be clinically effective in the treatment of patients with non-small cell lung cancer (NSCLC). However, the therapeutic effect of gefitinib is often limited by the development of gefitinib resistance. MicroRNAs (miRNAs), a group of small non-coding RNAs, have been demonstrated to be frequently dysregulated in human malignancies. For instance, the downregulation of miR-506-3p has been reported in NSCLC patients. The aim of the present study was to determine the role and underlying molecular mechanism of miR-506-3p in the regulation of gefitinib sensitivity in NSCLC. A gefitinib-resistant PC-9 (PC-9GR) cell line was established, and reduced miR-506-3p expression was observed in PC-9GR cells as compared with that in parental cells. The results of cell cytotoxicity and cell apoptosis assays indicated that PC-9GR cells were more sensitive to gefitinib following the transfection with an miR-506-3p mimic, while transfection with an miR-506-3p antagonist reduced the sensitivity of PC-9GR cells to gefitinib. It was further revealed that Yes-associated protein 1 (YAP1) was directly suppressed by miR-506-3p in PC-9GR cells. The elevated sensitivity of PC-9GR cells to gefitinib following transfection with the miR-506-3p mimic was counteracted by the overexpression of YAP1. Furthermore, an inverse correlation between the miR-506-3p and YAP1 mRNA levels was detected in lung adenocarcinoma specimens. Collectively, the results of the present study suggested that the downregulation of miR-506-3p contributes to gefitinib resistance, and thus, the restoration of miR-506-3p may be a potential therapeutic approach for overcoming NSCLC gefitinib resistance.