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MiR-181a contributes gefitinib resistance in non-small cell lung cancer cells by targeting GAS7
Wei Ping1, Yi Gao1, Xiaowu Fan1
1Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Abstract:
Tyrosine kinase inhibitors (TKIs) exert potent therapeutic efficacy in non-small cell lung cancers (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations. However, a major impediment for the effective treatment is the development of drug resistance. Some evidence supports a role for miRNAs in modulating NSCLC TKIs resistance. Here we show that miR-181a is significantly up-regulated in gefitinib-resistant cells compared with gefitinib-sensitive cells. Upregulation of miR-181a caused resistance of gefitinib, whereas downregulation of miR-181a sensitized NSCLC cells to gefitinib. Furthermore, the miR-181a plasma levels were significantly increased in acquired gefitinib resistant NSCLC patients compared with the plasma levels prior to gefitinib treatment in each patient. Bioinformatics analysis and luciferase reporter assay showed that growth arrest-specific 7 (GAS7) was a direct target gene of miR-181a. A significant inverse correlation between the expression of miR-181a and GAS7 was identified in NSCLC tissues. Downregulation of GAS7 expression could antagonize gefitinib re-sensitivity in PC9GR mediated by knockdown of miR-181a via AKT/ERK pathways and epithelial-to-mesenchymal transition markers. Additionally, GAS7 expression was downregulated in a large cohort of NSCLC patients, and a high mRNA level of GAS7 was associated with improved overall survival. Collectively, our findings provide a novel basis for using miR-181a/GAS7-based therapeutic strategies to reverse gefitinib resistance in NSCLC.
Insights
MicroRNA-181a (miR-181a) upregulation drives gefitinib resistance in non-small cell lung cancer (NSCLC). Targeting miR-181a and its downstream target GAS7 may reverse this resistance, offering new therapeutic avenues for NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tyrosine kinase inhibitors (TKIs) are effective against EGFR-mutated NSCLC.
- Drug resistance remains a significant challenge in NSCLC treatment.
- MicroRNAs (miRNAs) are implicated in modulating TKI resistance.
Purpose of the Study:
- To investigate the role of miR-181a in gefitinib resistance in NSCLC.
- To identify the molecular mechanisms underlying miR-181a-mediated gefitinib resistance.
- To explore the therapeutic potential of targeting the miR-181a/GAS7 axis.
Main Methods:
- Comparative analysis of miR-181a levels in gefitinib-sensitive and resistant NSCLC cells and patient plasma.
- Functional studies involving miR-181a upregulation and downregulation.
- Bioinformatics analysis and luciferase reporter assays to identify miR-181a targets.
- Correlation analysis of miR-181a and GAS7 expression in NSCLC tissues.
- Investigation of downstream signaling pathways (AKT/ERK) and EMT markers.
Main Results:
- miR-181a was significantly upregulated in gefitinib-resistant NSCLC cells and patient plasma.
- Upregulation of miR-181a induced gefitinib resistance; downregulation sensitized cells.
- GAS7 was identified as a direct target of miR-181a, with inverse expression correlation.
- GAS7 downregulation antagonized gefitinib re-sensitization mediated by miR-181a knockdown.
- Low GAS7 expression correlated with poorer survival in NSCLC patients.
Conclusions:
- miR-181a plays a crucial role in the development of gefitinib resistance in NSCLC.
- The miR-181a/GAS7 axis represents a potential therapeutic target for overcoming gefitinib resistance.
- Targeting this axis may restore sensitivity to TKIs in resistant NSCLC.
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