MiR-181a contributes gefitinib resistance in non-small cell lung cancer cells by targeting GAS7

Biochem Biophys Res Commun. 2018 Jan 22;495(4):2482-2489. doi: 10.1016/j.bbrc.2017.12.096. Epub 2017 Dec 18.


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.

Keywords: Gefitinib resistance; Growth arrest specific 7; MicroRNA-181a; Non-small cell lung cancer; Tyrosine kinase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / metabolism
  • China / epidemiology
  • Drug Resistance, Neoplasm*
  • Female
  • Gefitinib
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / mortality
  • Male
  • MicroRNAs / metabolism*
  • Nerve Tissue Proteins / metabolism*
  • Protein Kinase Inhibitors / toxicity
  • Quinazolines / therapeutic use*
  • Risk Factors
  • Survival Rate


  • Biomarkers, Tumor
  • GAS7 protein, human
  • MIrn181 microRNA, human
  • MicroRNAs
  • Nerve Tissue Proteins
  • Protein Kinase Inhibitors
  • Quinazolines
  • Gefitinib