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

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.

• Authors: De-Wei Wu, Yao-Chen Wang, Lee Wang, Chih Yi Chen, Huei Lee
• Journal: Theranostics (Theranostics) Vol. 8 Issue 5 Pg. 1256-1269 ( 2018) ISSN: 1838-7640 [Electronic] Australia
• PMID: 29507618 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• MIRN630 microRNA, human
• MicroRNAs
• Phosphoproteins
• Protein Kinase Inhibitors
• RNA, Messenger
• Sp1 Transcription Factor
• Transcription Factors
• YAP-Signaling Proteins
• YAP1 protein, human
• bcl-Associated Death Protein
• Phosphoserine
• EGFR protein, human
• ErbB Receptors
• Extracellular Signal-Regulated MAP Kinases
• Gefitinib

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Adenocarcinoma of Lung (drug therapy, genetics)
• Animals
• Cell Line, Tumor
• Disease-Free Survival
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (genetics)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Feedback, Physiological
• Female
• Gefitinib (pharmacology, therapeutic use)
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (genetics, metabolism)
• Middle Aged
• Mutation (genetics)
• Phosphoproteins (genetics, metabolism)
• Phosphorylation (drug effects)
• Phosphoserine (metabolism)
• Promoter Regions, Genetic (genetics)
• Protein Binding
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• RNA, Messenger (genetics, metabolism)
• Sp1 Transcription Factor (metabolism)
• Transcription Factors
• Up-Regulation (drug effects, genetics)
• YAP-Signaling Proteins
• bcl-Associated Death Protein (metabolism)