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γ-Catenin expression is reduced or absent in a subset of human lung cancers and re-expression inhibits transformed cell growth

Oncogene volume 21, pages 7497–7506 (2002)Cite this article

Abstract

Lung cancer is a heterogeneous disease categorized into multiple subtypes of cancers which likely arise from distinct patterns of genetic alterations and disruptions. Precedent exists for a role of β-catenin, a downstream component of the Wnt signaling pathway that serves as a transcriptional co-activator with TCF/LEF, in several human cancers including colon carcinomas. In this study, we observed that β-catenin was highly and uniformly expressed in a panel of 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 ∼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 (TSA), 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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Acknowledgements

These studies were supported by NIH grants DK19928 and CA58187 to LE Heasley and a VA Career Development Award 0001 to RA Winn. We appreciate the generous gifts of pCDNA3-dnTCF (a human Tcf-4E with an in frame N terminal deletion of amino acids 2–53) and pCDNA3-CA-β-catenin expression vectors (Myc-tagged human β-catenin with an in-frame N-terminal deletion of amino acids 29–48) from Drs Osamu Tetsu and Frank McCormick and the pCDNA3-γ-catenin expression vector kindly provided by Dr Eric Fearon. We also thank Dan Merrick and Raphael Nemenoff for many helpful discussions. In addition, we also greatly appreciate assistance with the immunofluorescence experiments by Barbara Helfrich and immunohistochemistry by Mysan Le.

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Authors and Affiliations

  1. Veterans Administration Medical Center, Denver, 80220, Colorado, CO, USA

    Robert A Winn & York E Miller

  2. Department of Medicine, University of Colorado Health Sciences Center, Denver, 80262, Colorado, CO, USA

    Robert A Winn, Roy M Bremnes, Lynne Bemis, Wilbur A Franklin, York E Miller, Carlyne Cool & Lynn E Heasley

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  1. Robert A Winn
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Correspondence to Robert A Winn.

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Winn, R., Bremnes, R., Bemis, L. et al. γ-Catenin expression is reduced or absent in a subset of human lung cancers and re-expression inhibits transformed cell growth. Oncogene 21, 7497–7506 (2002). https://doi.org/10.1038/sj.onc.1205963

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