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Medical Sciences
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 , and Harry A. Drabkin ^* 

^*Division of Medical Oncology, Departments of Biometrics/Preventive Medicine and Pathology, University of Colorado Health Sciences and Cancer Centers, 4200 East 9th Avenue, Denver, CO 80262; Institut de Biologie Moléculaire et d'Ingénierie Génétique, EA 2224, Université de Poitiers, 40 Avenue du Recteur Pineau, 86022 Poitiers Cédex, France; Laboratoire de Pathologie Cellulaire, Institut National de la Santé et de la Recherche Médicale 9924, Centre Hospitalo-Universitaire Albert Michallon, F-38043 Grenoble, France; ^¶Department of Cell and Developmental Biology and ^||Division of Gastroenterology, Department of Genetics, and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104-6100; ^**Department of Pathology and Center for Reproductive Sciences, Columbia University College of Physicians and Surgeons, New York, NY 10032; and Department of Pathology, Johns Hopkins Medical Center, Baltimore, MD 21231

Communicated by David M. Prescott, University of Colorado, Boulder, CO, July 3, 2003 (received for review April 9, 2003)

E-cadherin loss in cancer is associated with de-differentiation, invasion, and metastasis. Drosophila DE-cadherin is regulated by Wnt/-catenin signaling, although this has not been demonstrated in mammalian cells. We previously reported that expression of WNT7a, encoded on 3p25, was frequently downregulated in lung cancer, and that loss of E-cadherin or -catenin was a poor prognostic feature. Here we show that WNT7a both activates E-cadherin expression via a -catenin specific mechanism in lung cancer cells and is involved in a positive feedback loop. Li⁺, a GSK3 inhibitor, led to E-cadherin induction in an inositol-independent manner. Similarly, exposure to mWNT7a specifically induced free -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/-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.

To whom correspondence should be addressed. E-mail: harry.drabkin{at}uchsc.edu.

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