MiR-873 inhibition enhances gefitinib resistance in non-small cell lung cancer cells by targeting glioma-associated oncogene homolog 1

Thorac Cancer. 2018 Oct;9(10):1262-1270. doi: 10.1111/1759-7714.12830. Epub 2018 Aug 20.

Abstract

Background: The five-year survival rate of non-small cell lung cancer (NSCLC) patients is very low. MiR-873 is involved in the growth, metastasis, and differentiation of tumors. Herein, we determined the target gene and influence of miR-873 in NSCLC.

Methods: MiRanda and Targetscan websites were used to predict the target gene of miR-873 in NSCLC. Luciferase activity was examined using a dual luciferase reporter gene assay kit. The viability, tube formation, and proliferation of cells were analyzed by cell counting kit-8, angiogenic analysis, and flow cytometry, respectively. The levels of miR-873 and GLI1 were evaluated using quantitative real-time PCR and Western blot assays.

Results: Low levels of GLI1 and high levels of miR-873 were observed in an NSCLC cell line (PC9) highly sensitive to EGFR-tyrosine kinase inhibitors. There was a negative correlation between miR-873 and GLI1 expression in PC9 and PC9/GR cells. The inhibition of miR-873 enhanced GLI1 levels. MiR-873 expression was inhibited by gefitinib. Gefitinib markedly reduced the viability, tube formation, and cell number in PC9 cells. However, suppression of miR-873 enhanced the resistance and knockdown of GLI1 enhanced the sensitivity of PC9 cells to gefitinib.

Conclusions: GLI1 is a target gene of miR-873 in NSCLC. The inhibition of miR-873 increased gefitinib resistance of NSCLC cells via the upregulation of GLI1. These results indicate that miR-873-GLI1 signaling is involved in gefitinib resistance in NSCLC.

Keywords: Angiogenesis; GLI1; miR-873; non-small cell lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Drug Resistance, Neoplasm
  • Gefitinib / pharmacology*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • MicroRNAs / antagonists & inhibitors*
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Transfection
  • Zinc Finger Protein GLI1 / genetics*
  • Zinc Finger Protein GLI1 / metabolism

Substances

  • Antineoplastic Agents
  • GLI1 protein, human
  • MIRN873 microRNA, human
  • MicroRNAs
  • Zinc Finger Protein GLI1
  • Gefitinib