The role of retinoid X receptor mRNA expression in Barrett's esophagus and Barrett's associated adenocarcinoma of the esophagus

Abstract

Objective The Barrett's multistage process is characterized histopathologically by progression from Barrett's intestinal metaplasia to Barrett's esophagus with dysplasia and ultimately adenocarcinoma. Understanding of the molecular alterations in this multistage process may contribute to improved diagnosis and treatment. Retinoid X Receptors (RXR) play an important role m regulating the morphogenesis, development, growth, and differentiation of cells. Alterations in RXR expression have been observed in a variety of solid tumors, however the role in Barrett's esophagus d ~ . s e has yet to be determined. Aim of this study was to assess the prevalence and timing of RXR mRNA expression in Barrett's metaplasia-dysplasiaadenocarcinoma sequence and to determine its role for the development and progression of this disease. Methods We analyzed the mRNA expression of all 3 RXR subtypes (RXRalpha, RXR-beta, RXR-gamma) by using a quantitative real-time RT-PCR method (Taqman) in 108 specimens from 19 patients with Barrett's esophagus without carcinoma (BE-group), 20 patients with Barrett's associated adenocarcinoma (F.A-group), and a control group of 10 patients without evidence of gastro-esophageal reflux disease (CG). Results RXR-alpha mRNA expression was significantly decreased (p<0.001; Kruskal-Walhs test), and RXRgamma (p<0.001) was significantly increased at higher stages in Barrett's esophgns disease. gXR-beta expression was highest in Barrett's tissues and significantly increased compared to normal squamous tissues (p = 0.01, Wilcoxon test) and adenocarinoma tissues (p = 0.018, Mann-Whitney test). RXR-alpha and RXR-beta mRNA expression were significantly associated in normal sqnamons esophagus tissues (r2 = 0.49; p<0.001; Spearman test), Barratt's tissues (r2 ~ 0.63; p<0.001), and adenocarcinoma tissues (r2 = 0.68; p = 0.001). There were significant differences in RXR-alpha (p~0.011) and RXR-beta (p=O.O05) mRNA expression in histopathologically normal squamons esophagus tissues in patients with cancer and the normal control group(CG). Conclusions These findings suggest that alterations in the mRNA expression of all 3 RXR subtypes are frequent events in the development and progression of Barrett's esophagus and associated adenocarcinoma, that qnantitation of RXR mRNA expression may be useful biomarkers for this disease, and that a widespread held-effect is present in the normal esophagus of patients with esophageal adenocarcinoma.