Downregulation of Dkk3 activates beta-catenin/TCF-4 signaling in lung cancer

Carcinogenesis. 2008 Jan;29(1):84-92. doi: 10.1093/carcin/bgm267. Epub 2007 Nov 28.

Abstract

Although the oncogenic role of the Wnt/beta-catenin pathway is well defined, it remains unclear how this pathway is aberrantly activated in lung cancer. We found that Dickkopf (Dkk)-3, a member of Dkk family of Wnt antagonists, is frequently inactivated in lung cancer and plays a role in suppressing lung cancer cell growth through inhibition of beta-catenin/T-cell factor (TCF)-4 signaling. Dkk3 is the only Dkk family member abundantly expressed in normal lung, but silenced by promoter hypermethylation in a large fraction of lung cancer cell lines and lung tumors. Downregulation of Dkk3 was correlated with tumor progression and expression of nuclear beta-catenin in lung tumors. Ectopic expression of Dkk3 in lung cancer cells with Dkk3 hypermethylation induced apoptosis and inhibited TCF-4 activity as well as nuclear accumulation of beta-catenin and expression of TCF-4 targets c-Myc and cyclin D1. Furthermore, small interference RNA knock down of Dkk3 in cells lacking Dkk3 hypermethylation was sufficient to promote cell proliferation, beta-catenin nuclear translocation and expression of c-Myc. These observations suggested that epigenetic inactivation of Dkk3 activates the Wnt/beta-catenin pathway, thereby promoting the growth of lung cancer cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Chemokines
  • Down-Regulation*
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Lung Neoplasms / metabolism*
  • Signal Transduction*
  • TCF Transcription Factors / metabolism*
  • Transcription Factor 7-Like 2 Protein
  • beta Catenin / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Chemokines
  • DKK3 protein, human
  • Intercellular Signaling Peptides and Proteins
  • TCF Transcription Factors
  • TCF7L2 protein, human
  • Transcription Factor 7-Like 2 Protein
  • beta Catenin