WNT7a induces E-cadherin in lung cancer cells

Tatsuo Ohira, Robert M. Gemmill, Kevin Ferguson, Sophie Kusy, Joëlle Roche, Elisabeth Brambilla, Chan Zeng, Anna Baron, Lynne Bemis, Paul Erickson, Elizabeth Wilder, Anil Rustgi, Jan Kitajewski, Edward Gabrielson, Roy Bremnes, Wilbur Franklin, Harry A. Drabkin

Research output: Contribution to journalArticle

140 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)10429-10434
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number18
DOIs
StatePublished - Sep 2 2003

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    Ohira, T., Gemmill, R. M., Ferguson, K., Kusy, S., Roche, J., Brambilla, E., Zeng, C., Baron, A., Bemis, L., Erickson, P., Wilder, E., Rustgi, A., Kitajewski, J., Gabrielson, E., Bremnes, R., Franklin, W., & Drabkin, H. A. (2003). WNT7a induces E-cadherin in lung cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 100(18), 10429-10434. https://doi.org/10.1073/pnas.1734137100