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Down-regulation of DUSP6 expression in lung cancer: its mechanism and potential role in carcinogenesis

Koji Okudela1, Takuya Yazawa, Tetsukan Woo

  • 1Department of Pathology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-Ku, 236-0004 Yokohama, Japan.

The American Journal of Pathology
|July 18, 2009
PubMed

Insights

Oncogenic KRAS suppresses airway cell growth, revealing a novel tumor suppressor, DUSP6. DUSP6 inactivation promotes lung cancer progression by reducing its growth-suppressive function.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Biology

Background:

  • Oncogenic KRAS (KRAS/V12) significantly inhibits immortalized airway epithelial cell (NHBE-T) growth.
  • This suppression differs from p53/RB-induced senescence, suggesting a novel KRAS-downstream tumor suppressor.

Purpose of the Study:

  • To identify novel tumor suppressors acting downstream of oncogenic KRAS.
  • To investigate the role of DUSP6 in lung cancer development.

Main Methods:

  • Comprehensive gene expression analysis to identify KRAS/V12-modulated genes.
  • Functional assays using dominant-negative DUSP6 mutants.
  • Analysis of DUSP6 expression in lung cancer cell lines and primary tumors.
  • Loss of heterozygosity analysis at the DUSP6 locus.

Main Results:

  • DUSP6, a negative regulator of the RAS-ERK pathway, was identified as a key target.
  • DUSP6 restoration suppressed cellular growth in lung cancer cells.
  • Decreased DUSP6 expression correlated with increased tumor growth activity and histological grade in primary lung cancers.
  • Loss of heterozygosity at the DUSP6 locus was observed in 17.7% of cases, linked to reduced expression.

Conclusions:

  • DUSP6 functions as a tumor suppressor that inhibits cell growth.
  • Inactivation of DUSP6 contributes to lung cancer progression.
  • DUSP6 is a novel factor involved in KRAS-driven carcinogenesis.

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