TY - JOUR
T1 - WNT7a induces E-cadherin in lung cancer cells
AU - Ohira, Tatsuo
AU - Gemmill, Robert M.
AU - Ferguson, Kevin
AU - Kusy, Sophie
AU - Roche, Joëlle
AU - Brambilla, Elisabeth
AU - Zeng, Chan
AU - Baron, Anna
AU - Bemis, Lynne
AU - Erickson, Paul
AU - Wilder, Elizabeth
AU - Rustgi, Anil
AU - Kitajewski, Jan
AU - Gabrielson, Edward
AU - Bremnes, Roy
AU - Franklin, Wilbur
AU - Drabkin, Harry A.
PY - 2003/9/2
Y1 - 2003/9/2
N2 - E-cadherin loss in cancer is associated with de-differentiation, invasion, and metastasis. Drosophila DE-cadherin is regulated by Wnt/β-catenin signaling, although this has not been demonstrated in mammalian cells. We previously reported that expression of WNT7a, encoded on 3p25, was frequently down-regulated in lung cancer, and that loss of E-cadherin or β-catenin was a poor prognostic feature. Here we show that WNT7a both activates E-cadherin expression via a β-catenin specific mechanism in lung cancer cells and is involved in a positive feedback loop. Li+, a GSK3β inhibitor, led to E-cadherin-induction an inositol-independent manner. Similarly, exposure to mWNT7a specifically induced free β-catenin and E-cadherin. Among known transcriptional suppressors of E-cadherin, ZEB1 was uniquely correlated with E-cadherin loss in lung cancer cell lines, and its inhibition by RNA interference resulted in E-cadherin induction. Pharmacologic reversal of E-cadherin and WNT7a losses was achieved with Li+, histone deacetylase inhibition, or in some cases only with combined inhibitors. Our findings provide support that E-cadherin induction by WNT/β-catenin signaling is an evolutionarily conserved pathway operative in lung cancer cells, and that loss of WNT7a expression may be important in lung cancer development or progression by its effects on E-cadherin.
AB - E-cadherin loss in cancer is associated with de-differentiation, invasion, and metastasis. Drosophila DE-cadherin is regulated by Wnt/β-catenin signaling, although this has not been demonstrated in mammalian cells. We previously reported that expression of WNT7a, encoded on 3p25, was frequently down-regulated in lung cancer, and that loss of E-cadherin or β-catenin was a poor prognostic feature. Here we show that WNT7a both activates E-cadherin expression via a β-catenin specific mechanism in lung cancer cells and is involved in a positive feedback loop. Li+, a GSK3β inhibitor, led to E-cadherin-induction an inositol-independent manner. Similarly, exposure to mWNT7a specifically induced free β-catenin and E-cadherin. Among known transcriptional suppressors of E-cadherin, ZEB1 was uniquely correlated with E-cadherin loss in lung cancer cell lines, and its inhibition by RNA interference resulted in E-cadherin induction. Pharmacologic reversal of E-cadherin and WNT7a losses was achieved with Li+, histone deacetylase inhibition, or in some cases only with combined inhibitors. Our findings provide support that E-cadherin induction by WNT/β-catenin signaling is an evolutionarily conserved pathway operative in lung cancer cells, and that loss of WNT7a expression may be important in lung cancer development or progression by its effects on E-cadherin.
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U2 - 10.1073/pnas.1734137100
DO - 10.1073/pnas.1734137100
M3 - Article
C2 - 12937339
AN - SCOPUS:0042337389
SN - 0027-8424
VL - 100
SP - 10429
EP - 10434
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 18
ER -