Comprehensive expression analysis of retinoic acid receptors and retinoid X receptors in non-small cell lung cancer:: implications for tumor development and prognosis

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: RARalpha 100%, RARbeta 94%, RARgamma 94%, RXRalpha 100%, RXRbeta 100% and RXRgamma 92%. Levels of mRNA expression in tumor tissues compared with matching normal-appearing tissue were equal or reduced with the following frequencies: RARalpha 76.1%, RARbeta 59.1%, RARgamma 39.8%, RXRalpha 67.1%, RXRbeta 54.5% and RXRgamma 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.