Carcinogenesis Advance Access originally published online on November 28, 2007
Carcinogenesis 2008 29(1):84-92; doi:10.1093/carcin/bgm267
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Downregulation of Dkk3 activates β-catenin/TCF-4 signaling in lung cancer
Department of Pharmacology
1 Department of Pathology
2 Department of Surgery, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
* To whom correspondence should be addressed. Tel: +412 623 1009; Fax: +412 623 7778; Email: zhanglx{at}upmc.edu
Although the oncogenic role of the Wnt/β-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 β-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 β-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 β-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, β-catenin nuclear translocation and expression of c-Myc. These observations suggested that epigenetic inactivation of Dkk3 activates the Wnt/β-catenin pathway, thereby promoting the growth of lung cancer cells.
Abbreviations: BrdU, bromodeoxyuridine; Dkk, Dickkopf; MSP, methylation-specific polymerase chain reaction; NL, normal lymphocyte; NSCLC, non-small-cell lung cancer; PCR, polymerase chain reaction; SAGE, serial analysis of gene expression; siRNA, small interference RNA; TCF, T-cell factor; 5-aza-dC, 5-aza-2'-deoxycytidine
Received July 24, 2007; revised November 13, 2007; accepted November 18, 2007.
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