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γ-Catenin Expression Is Reduced or Absent in a Subset of Human Non-small Cell Lung Cancers, and Its Re-expression Inhibits Cell Growth*

Robert A. Winn, MD; Lynn E. Heasley, PhD
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*From the Veterans Administration Medical Center, Denver, Denver; and Department of Medicine, University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: Robert A. Winn, MD, Division of Pulmonary and Critical Care, C272, University of Colorado Health Sciences Center, 4200 E. Ninth Ave, Denver, CO 80262; e-mail: robert.winn@uchsc.edu



Chest. 2004;125(5_suppl):122S-123S. doi:10.1378/chest.125.5_suppl.122S
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Lung cancer is a heterogeneous disease categorized into multiple subtypes of cancers that likely arise from distinct patterns of genetic alterations and disruptions.14 Precedent exists for a role of β-catenin, a downstream component of the Wnt signaling pathway that serves as a transcriptional co-activator with T-cell transcription factor (TCF)/lymphoid enhancer factor (TCF/Lef), in several human cancers including colon carcinomas.1,58 In this study, we observed that β-catenin was highly and uniformly expressed in a panel of non-small cell lung cancer (NSCLC) cell lines and primary lung tumors. By contrast, γ-catenin was weakly expressed or absent in several NSCLC cell lines, and immunohistochemical analysis of primary NSCLC tumors revealed negligible to weak γ-catenin staining in approximately 30% of the specimens. Treatment of NSCLC cells expressing reduced γ-catenin protein with 5-aza-2′-deoxycytidine (5aza2dc), a DNA methylation inhibitor, or trichostatin A, a histone deacetylase inhibitor, increased γ-catenin protein content in NSCLC cells with low γ-catenin expression. Significantly, the activity of a β-catenin/TCF-dependent luciferase reporter was markedly elevated in the NSCLC cell lines that underexpressed γ-catenin relative to those lines that highly expressed γ-catenin. Moreover, transfection of these cells with a γ-catenin expression plasmid reduced the elevated TCF activity by 85%, and strongly inhibited cell growth on tissue culture plastic as well as anchorage-independent growth in soft agar. This study shows that γ-catenin can function as an inhibitor of β-catenin/TCF-dependent gene transcription and highlights γ-catenin as a potentially novel tumor suppressor protein in a subset of human NSCLC cancers.

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