(Chest. 2004;125:122S-123S.)
© 2004
American College of Chest Physicians
-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 and
Lynn E. Heasley, PhD
* 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{at}uchsc.edu
Lung cancer is a heterogeneous disease categorized into multiple subtypes of cancers that likely arise from distinct patterns of genetic alterations and disruptions.1234 Precedent exists for a role of ß-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.15678 In this study, we observed that ß-catenin was highly and uniformly expressed in a panel of non-small cell lung cancer (NSCLC) cell lines and primary lung tumors. By contrast, 
-catenin was weakly expressed or absent in several NSCLC cell lines, and immunohistochemical analysis of primary NSCLC tumors revealed negligible to weak -catenin staining in approximately 30% of the specimens. Treatment of NSCLC cells expressing reduced -catenin protein with 5-aza-2'-deoxycytidine (5aza2dc), a DNA methylation inhibitor, or trichostatin A, a histone deacetylase inhibitor, increased -catenin protein content in NSCLC cells with low -catenin expression. Significantly, the activity of a ß-catenin/TCF-dependent luciferase reporter was markedly elevated in the NSCLC cell lines that underexpressed -catenin relative to those lines that highly expressed -catenin. Moreover, transfection of these cells with a -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 -catenin can function as an inhibitor of ß-catenin/TCF-dependent gene transcription and highlights -catenin as a potentially novel tumor suppressor protein in a subset of human NSCLC cancers.
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Footnotes
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Abbreviations: NSCLC = non-small cell lung cancer; TCF = T-cell transcription factor
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References
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- de La Coste, A, Romagnolo, B, Billuart, P, et al (1998) Somatic mutations of the ß-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA 95,8847-8851[Abstract/Free Full Text]
- Graziano, SL, Gamble, GP, Newman, NB, et al Prognostic significance of K-ras codon 12 mutations in patients with resected stage I and II non-small-cell lung cancer. J Clin Oncol 1999;17,668-675[Abstract/Free Full Text]
- Greenlee, R, Hill-Harmon, MB, Murray, T, et al Cancer statistics, 2001. CA Cancer J Clin 2001;51,15-36[Abstract/Free Full Text]
- Hsieh, ET, Shepherd, FA, Tsao, MS Co-expression of epidermal growth factor receptor and transforming growth factor-
is independent of ras mutations in lung adenocarcinoma. Lung Cancer 2000;29,151-157[ISI][Medline]
- Huber, OKR, McLaughlin, J, Ohsugi, M, et al Nuclear localization of ß-catenin by interaction with transcription factor LEF-1. Mech Dev 1996;59,3-10[CrossRef][ISI][Medline]
- Pirinen, RT, Hirvikoski, P, Johansson, RT, et al Reduced expression of -catenin, ß-catenin, and -catenin is associated with high cell proliferative activity and poor differentiation in non-small cell lung cancer. J Clin Pathol 2001;54,391-395[Abstract/Free Full Text]
- Polakis, P Wnt signaling and cancer. Genes Dev 2000;14,1837-1851[Free Full Text]
- Ueda, M, Gemmill, RM, West, J, et al Mutations of the ß- and -catenin genes are uncommon in human lung, breast, kidney, cervical and ovarian carcinomas. Br J Cancer 2001;85,64-68[CrossRef][ISI][Medline]
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