Theranostics 2018; 8(5):1256-1269. doi:10.7150/thno.22048

Research Paper

A low microRNA-630 expression confers resistance to tyrosine kinase inhibitors in EGFR-mutated lung adenocarcinomas via miR-630/YAP1/ERK feedback loop

De-Wei Wu1#, Yao-Chen Wang2#, Lee Wang3, Chih Yi Chen4, Huei Lee1✉

1. Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
2. Department of Internal Medicine, Chung Shan Medical Hospital, Taichung, Taiwan
3. School of Public Health,Chung Shan Medical University, Taichung, Taiwan
4. Department of Surgery, Chung Shan Medical Hospital, Taichung, Taiwan
#D.-W. Wu and Y.-C. Wang contributed equally to this work.

Abstract

Purpose: MicroRNA-630 plays dual roles in apoptosis and drug resistance in human cancers. However, the role of miR-630 in resistance to tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma remains to be elucidated.

Methods: Manipulation of miR-630 and its targeted gene YAP1 and/or combination of inhibitor treatments was performed to explore whether low miR-630 could confer TKI resistance due to de-targeting YAP1, and this could decrease proapoptotic protein Bad expression through the miR-630/YAP1/ERK feedback loop. A retrospective study was conducted to examine whether the expression of miR-630 and YAP1 could be associated with TKI therapeutic response in patients with lung adenocarcinoma.

Results: Low miR-630 expression may confer TKI resistance via increased SP1 binding to the miR-630 promoter due to ERK activation by YAP1 de-targeting. Persistent activation of ERK signaling via the miR-630/YAP1/ERK feedback loop may be responsible for TKI resistance in EGFR-mutated cells. Moreover, a decrease in Bad expression by its phosphorylation at Serine 75 through ERK activation conferred low miR-630-mediated TKI resistance by modulating the apoptotic pathway. Xenographic tumors induced by miR-630-knockdown PC9 and PC9GR cells in nude mice were nearly suppressed by the combination of gefitinib with the YAP1 inhibitor verteporfin or an MEK/ERK inhibitor AZD6244. Patients with low miR-630 and high YAP1 expressing tumors had a higher prevalence of unfavorable responses to TKI therapy and poorer outcomes when compared with their counterparts.

Conclusion: MiR-630 may be a potential biomarker for the prediction of TKI therapeutic response and outcome in patients with lung adenocarcinoma.

Keywords: MiR-630, YAP1, TKI resistance, and lung adenocarcinoma

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How to cite this article:
Wu DW, Wang YC, Wang L, Chen CY, Lee H. A low microRNA-630 expression confers resistance to tyrosine kinase inhibitors in EGFR-mutated lung adenocarcinomas via miR-630/YAP1/ERK feedback loop. Theranostics 2018; 8(5):1256-1269. doi:10.7150/thno.22048. Available from http://www.thno.org/v08p1256.htm