TY - JOUR
T1 - Downregulation of Dkk3 activates β-catenin/TCF-4 signaling in lung cancer
AU - Yue, Wen
AU - Sun, Quanhong
AU - Dacic, Sanja
AU - Landreneau, Rodney J.
AU - Siegfried, Jill M.
AU - Yu, Jian
AU - Zhang, Lin
PY - 2008/1
Y1 - 2008/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=38849145619&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=38849145619&partnerID=8YFLogxK
U2 - 10.1093/carcin/bgm267
DO - 10.1093/carcin/bgm267
M3 - Article
C2 - 18048388
AN - SCOPUS:38849145619
SN - 0143-3334
VL - 29
SP - 84
EP - 92
JO - Carcinogenesis
JF - Carcinogenesis
IS - 1
ER -