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Sci Rep. 2017 Jan 13;7:40847. doi: 10.1038/srep40847.

Targeting the miR-200c/LIN28B axis in acquired EGFR-TKI resistance non-small cell lung cancer cells harboring EMT features.

Author information

1
Departments of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
2
Departments of Bioinformatics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
3
Departments of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Abstract

MicroRNA (miR)-200 family members (miR-200s) are frequently silenced in advanced cancer and have been implicated in the process of epithelial-to-mesenchymal transition (EMT). We previously reported that miR-200s were silenced through promoter methylation in acquired EGFR-tyrosine kinase inhibitor (TKI) resistant non-small cell lung cancer (NSCLC) cells harboring EMT features. In this study, we examined the functional role of miR-200s in NSCLC cells and investigated a novel approach to overcoming acquired EGFR-TKI resistance. In the analysis of NSCLC cell lines, each of the miR-200s expression-silenced cell lines showed promoter methylation. Significant correlations between miR-200c silencing and several oncogenic pathway alterations, including EMT-changes and LIN28B overexpression, were observed in the database analysis. In addition, EGFR-wild type cell lines had lower miR-200s expression levels than EGFR-mutant cell lines. The introduction of miR-200c using pre-miR-200c caused LIN28B suppression in cells with acquired EGFR-TKI resistance that harbored EMT features. Interestingly, both the introduction of miR-200c and the knockdown of LIN28B produced an antitumor effect in acquired EGFR-TKI resistance cells, whereas these manipulations were not effective in parental cells. The miR-200c/LIN28B axis plays an important role in cells with acquired resistance to EGFR-TKI that harbor EMT features and might be a useful therapeutic target for overcoming resistance.

PMID:
28084458
PMCID:
PMC5233972
DOI:
10.1038/srep40847
[Indexed for MEDLINE]
Free PMC Article

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