Low expression of Mig-6 is associated with poor survival outcome in NSCLC and inhibits cell apoptosis via ERK-mediated upregulation of Bcl-2

Oncol Rep. 2014 Apr;31(4):1707-14. doi: 10.3892/or.2014.3050. Epub 2014 Feb 24.


Mitogen-inducible gene-6 (Mig-6), an immediate early response gene, is a specific negative regulator of epidermal growth factor receptor (EGFR). Ablation of Mig-6 has been shown to induce tumor formation in various tissues, supporting the tumor suppressor function of Mig-6. However, little is known about the role of Mig-6 in non-small cell lung cancer (NSCLC) apoptosis, nor has the contribution of upregulated Mig-6 on biological behaviors of A549 and H157 cells previously been reported. The aim of the present study was to investigate the effects of exogenously transfected Mig-6 on proliferation, invasion and apoptosis of A549 and H157 cells and to identify novel underlying mechanisms of Mig-6-induced apoptosis. We used immunohistochemical staining to examine the expression of Mig-6 protein in NSCLC tissues. For evaluation of the prognostic value of Mig-6 expression to each clinicopathologic factor, Kaplan-Meier method and Cox's proportional hazards model were employed. Mig-6 low expression was correlated with a poor prognosis in patients with lung cancer. Patients with high expression of Mig-6 had a statistically significantly longer survival than those with low expression of Mig-6. Cox's regression analysis indicated that loss of Mig-6 expression was an independent, unfavorable prognostic factors. We utilized siRNA-targeting Mig-6 and Mig-6 overexpression plasmid to determine the effect of Mig-6 on lung cancer cells. Flow cytometry studies revealed Mig-6 overexpression promoted apoptosis in NSCLC cell lines. siRNA-mediated Mig-6 knockdown inhibited apoptosis of cancer cells, but this anti-apoptotic effect was abolished by inhibition of ERK. Upregulation of Mig-6 decreased the proliferation and invasive potential of transfected cells. Moreover, upregulation of Mig-6 inhibited proliferation and invasion of A549 and H157 cells. Collectively, our results showed that Mig-6 is a potential biomarker for evaluation of tumor prognosis of lung cancer. Mig-6 promotes apoptosis in lung cancer cells via the ERK pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Apoptosis / genetics*
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / genetics
  • Blotting, Western
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Cell Line, Tumor
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / mortality
  • Prognosis
  • Proportional Hazards Models
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction / genetics*
  • Tumor Suppressor Proteins / genetics*
  • Up-Regulation


  • Adaptor Proteins, Signal Transducing
  • Biomarkers, Tumor
  • ERRFI1 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Proteins
  • Extracellular Signal-Regulated MAP Kinases