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ETS2 mediated tumor suppressive function and MET oncogene inhibition in human non-small cell lung cancer

Mohamed Kabbout1, Melinda M Garcia1, Junya Fujimoto1

  • 1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|May 11, 2013
PubMed
Abstract

Insights

ETS2, a downregulated gene in lung cancer, acts as a tumor suppressor. Reduced ETS2 expression predicts shorter recurrence times and promotes cancer cell growth and invasion by activating the HGF/MET pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Regulation

Background:

  • ETS2 is an evolutionarily conserved transcription factor.
  • ETS2 is frequently deregulated in various cancers.
  • ETS2 is significantly downregulated in lung adenocarcinomas compared to normal lung tissue.

Purpose of the Study:

  • To investigate the functional role of ETS2 in lung cancer pathogenesis.
  • To determine the impact of ETS2 downregulation on lung adenocarcinoma development.
  • To elucidate the molecular mechanisms underlying ETS2's function in lung cancer.

Main Methods:

  • Transcriptome analysis of lung adenocarcinomas and normal lung tissues using Affymetrix Human Gene 1.0 ST platform.
  • Immunohistochemical (IHC) analysis of ETS2 protein expression in 201 non-small cell lung cancer (NSCLC) specimens.
  • RNA interference and overexpression studies to assess ETS2's effects on cell phenotypes and gene expression.
  • Statistical analysis of patient clinical outcomes based on ETS2 IHC expression.

Main Results:

  • ETS2 expression was significantly reduced in lung adenocarcinomas (P < 0.001).
  • Low ETS2 IHC expression correlated with shorter recurrence times in NSCLC (P = 0.009) and adenocarcinoma (P = 0.03).
  • ETS2 inhibited lung cancer cell growth, migration, and invasion (P < 0.05).
  • ETS2 knockdown led to significant activation of the HGF pathway (P < 0.001).
  • ETS2 suppressed MET phosphorylation; MET knockdown attenuated ETS2-mediated invasion (P < 0.05).
  • ETS2 knockdown augmented HGF-induced MET phosphorylation, migration, and invasion.

Conclusions:

  • ETS2 functions as a tumor suppressor in human NSCLC.
  • ETS2 inhibits lung cancer progression by suppressing the MET proto-oncogene.
  • Targeting the ETS2/MET pathway may offer therapeutic strategies for NSCLC.

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