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J. Biol. Chem., Vol. 280, Issue 20, 19625-19634, May 20, 2005

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Restoration of Wnt-7a Expression Reverses Non-small Cell Lung Cancer Cellular Transformation through Frizzled-9-mediated Growth Inhibition and Promotion of Cell Differentiation^*

Robert A. Winn¶, Lindsay Marek, Sun-Young Han, Karen Rodriguez, Nicole Rodriguez, Mandy Hammond, Michelle Van Scoyk, Henri Acosta, Justin Mirus, Nicholas Barry, Yvette Bren-Mattison, Terence J. Van Raay||, Raphael A. Nemenoff, and Lynn E. Heasley

From the Veterans Affairs Medical Center, Denver, Colorado 80220, the Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, and the ^||Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232

The Wnt signaling pathway is critical in normal development, and mutation of specific components is frequently observed in carcinomas of diverse origins. However, the potential involvement of this pathway in lung tumorigenesis has not been established. In this study, analysis of multiple Wnt mRNAs in non-small cell lung cancer (NSCLC) cell lines and primary lung tumors revealed markedly decreased Wnt-7a expression compared with normal short-term bronchial epithelial cell lines and normal uninvolved lung tissue. Wnt-7a transfection in NSCLC cell lines reversed cellular transformation, decreased anchorage-independent growth, and induced epithelial differentiation as demonstrated by soft agar and three-dimensional cell culture assays in a subset of the NSCLC cell lines. The action of Wnt-7a correlated with expression of the specific Wnt receptor Frizzled-9 (Fzd-9), and transfection of Fzd-9 into a Wnt-7a-insensitive NSCLC cell line established Wnt-7a sensitivity. Moreover, Wnt-7a was present in Fzd-9 immunoprecipitates, indicating a direct interaction of Wnt-7a and Fzd-9. In NSCLC cells, Wnt-7a and Fzd-9 induced both cadherin and Sprouty-4 expression and stimulated the JNK pathway, but not -catenin/T cell factor activity. In addition, transfection of gain-of-function JNK strongly inhibited anchorage-independent growth. Thus, this study demonstrates that Wnt-7a and Fzd-9 signaling through activation of the JNK pathway induces cadherin proteins and the receptor tyrosine kinase inhibitor Sprouty-4 and represents a novel tumor suppressor pathway in lung cancer that is required for maintenance of epithelial differentiation and inhibition of transformed cell growth in a subset of human NSCLCs.

Received for publication, August 16, 2004 , and in revised form, February 9, 2005.

^* This work was supported by Veterans Affairs Career Development Award RCD-0001 and National Institutes of Health Specialized Program of Research Excellence Lung Cancer Career Development Award P50 CA58187 and Grant CA103618. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Div. of Pulmonary and Critical Care Medicine, University of Colorado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO 80262. Tel.: 303-315-0011; Fax: 303-315-4852; E-mail: robert.winn{at}uchsc.edu.

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