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Biochem Biophys Res Commun. 2014 Mar 28;446(1):179-86. doi: 10.1016/j.bbrc.2014.02.073. Epub 2014 Feb 28.

miR-138-5p reverses gefitinib resistance in non-small cell lung cancer cells via negatively regulating G protein-coupled receptor 124.

Author information

1
Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
2
Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
3
Research Institute of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: Leojokea@ailiyun.com.
4
Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: fuxn2006@aliyun.com.

Abstract

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) such as gefitinib are clinically effective treatments for non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, therapeutic effect is ultimately limited by the development of acquired TKI resistance. MicroRNAs (miRNAs) represent a category of small non-coding RNAs commonly deregulated in human malignancies. The aim of this study was to investigate the role of miRNAs in gefitinib resistance. We established a gefitinib-resistant cell model (PC9GR) by continually exposing PC9 NSCLC cells to gefitinib for 6 months. MiRNA microarray screening revealed miR-138-5p showed the greatest downregulation in PC9GR cells. Re-expression of miR-138-5p was sufficient to sensitize PC9GR cells and another gefitinib-resistant NSCLC cell line, H1975, to gefitinib. Bioinformatics analysis and luciferase reporter assay showed that G protein-coupled receptor124 (GPR124) was a direct target of miR-138-5p. Experimental validation demonstrated that expression of GPR124 was suppressed by miR-138-5p on protein and mRNA levels in NSCLC cells. Furthermore, we observed an inverse correlation between the expression of miR-138-5p and GPR124 in lung adenocarcinoma specimens. Knockdown of GPR124 mimicked the effects of miR-138-5p on the sensitivity to gefitinib. Collectively, our results suggest that downregulation of miR-138-5p contributes to gefitinib resistance and that restoration of miR-138-5p or inhibition GPR124 might serve as potential therapeutic approach for overcoming NSCLC gefitinib resistance.

KEYWORDS:

G protein-coupled receptors; Gefitinib resistance; MicroRNA; Non-small cell lung cancer; Tyrosine kinase inhibitor

PMID:
24582749
DOI:
10.1016/j.bbrc.2014.02.073
[Indexed for MEDLINE]

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