Carcinogenesis Advance Access originally published online on December 23, 2004
Carcinogenesis 2005 26(3):525-530; doi:10.1093/carcin/bgi006
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Carcinogenesis vol.26 no.3 © Oxford University Press 2004; all rights reserved.
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Comprehensive expression analysis of retinoic acid receptors and retinoid X receptors in non-small cell lung cancer: implications for tumor development and prognosis
Department of Visceral and Vascular Surgery, University of Cologne, Joseph-Stelzmann Strasse 9, 50931 Cologne, Germany, 1 Response Genetics Inc., Los Angeles, CA 90033, USA and 2 Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine and USC/Kenneth Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
3 To whom correspondence should be addressed. Tel: +49 221 4784803; Fax: +49 212 67002; Email: jan.brabender{at}t-online.de
Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are important in regulating the development, growth and differentiation of cells and have inhibitory effects on non-small cell lung cancer (NSCLC) cell growth. A comprehensive analysis of all RAR and RXR subtypes mRNA expression in a large series of patients with NSCLC and their role in the development and progression of this disease is lacking. Using a quantitative real-time RT–PCR method, we analyzed the mRNA expression of all retinoid receptor subtypes in tumor and matching normal-appearing tissues of 88 patients with NSCLC. Gene expression in tumor tissues was detected with the following frequencies: RAR
100%, RARß 94%, RAR
94%, RXR 100%, RXRß 100% and RXR 92%. Levels of mRNA expression in tumor tissues compared with matching normal-appearing tissue were equal or reduced with the following frequencies: RAR 76.1%, RARß 59.1%, RAR 39.8%, RXR 67.1%, RXRß 54.5% and RXR 88.6%, and were significantly associated with any one other subtype. The probability of survival was significantly different among patients with low gene expression in no or any two subtypes, any three or four subtypes or any five or six subtypes (P = 0.004, log rank test). Multivariate analysis confirmed low gene expression status as a significant independent unfavorable prognostic factor (P = 0.015). Our results show that decreased expression of all RAR and RXR receptor subtypes is a frequent event in NSCLC. Widely co-regulated down-regulation of expression of all retinoid subclasses suggests a fundamental dysregulation of the retinoid pathway in this cancer. Quantitation of RAR and RXR mRNA expression levels in tumor tissue is a candidate prognostic marker and surrogate biomarker for chemopreventive trials in NSCLC.
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