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miR-124 modulates gefitinib resistance through SNAI2 and STAT3 in non-small cell lung cancer
Fa-Yong Hu1, Xiao-Nian Cao2, Qin-Zi Xu2
1Cancer Research Institute, Huazhong University of Science and Technology, Wuhan, 430030, China.
Abstract:
Gefitinib is used as a first-line treatment for advanced non-small cell lung cancer (NSCLC). Unfortunately, most NSCLC patients inevitably develop gefitinib resistance during treatment. In addition to EGFR mutation status, the mechanisms involved are largely unknown. In this study, we showed that miR-124, a tumor suppressor, was significantly down-regulated in gefitinib-resistant NSCLC patients and cell lines compared with gefitinib-sensitive patients and cell lines. In addition, the miR-124 depletion induced gefitinib resistance, and miR-124 overexpression sensitized gefitinib-resistant cells to gefitinib. Mechanistic analysis revealed that miR-124 decreased SNAI2 and STAT3 expression by directly targeting their 3'UTRs and that knocking down SNAI2 or STAT3 partly reversed the gefitinib resistance induced by miR-124 depletion. Our data demonstrate that the miR-124 plays a new critical role in acquired resistance to gefitinib and that the manipulation of miR-124 might provide a therapeutic strategy for reversing acquired gefitinib resistance.
Insights
MicroRNA-124 (miR-124) down-regulation contributes to gefitinib resistance in non-small cell lung cancer (NSCLC). Restoring miR-124 levels may overcome this resistance, offering a new therapeutic strategy for NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gefitinib is a first-line treatment for advanced non-small cell lung cancer (NSCLC).
- Acquired resistance to gefitinib is a major clinical challenge in NSCLC treatment.
- Mechanisms underlying gefitinib resistance, beyond EGFR mutation status, remain largely unknown.
Purpose of the Study:
- To investigate the role of microRNA-124 (miR-124) in acquired gefitinib resistance in NSCLC.
- To explore the potential of miR-124 as a therapeutic target for overcoming gefitinib resistance.
Main Methods:
- Comparative analysis of miR-124 expression in gefitinib-sensitive and resistant NSCLC patients and cell lines.
- Functional studies involving miR-124 depletion and overexpression in NSCLC cells.
- Mechanistic investigations using 3'UTR targeting assays to identify downstream targets of miR-124.
- Validation of target genes (SNAI2, STAT3) by knockdown experiments.
Main Results:
- miR-124 was significantly down-regulated in gefitinib-resistant NSCLC compared to sensitive counterparts.
- Depletion of miR-124 induced gefitinib resistance, while its overexpression sensitized resistant cells to gefitinib.
- miR-124 directly targets the 3'UTRs of SNAI2 and STAT3, reducing their expression.
- Knockdown of SNAI2 or STAT3 partially reversed the gefitinib resistance caused by miR-124 depletion.
Conclusions:
- miR-124 plays a critical role in the development of acquired gefitinib resistance in NSCLC.
- The miR-124/SNAI2/STAT3 axis is a key pathway involved in gefitinib resistance.
- Modulating miR-124 levels presents a promising therapeutic strategy for reversing acquired gefitinib resistance in NSCLC.
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