Su1160 Expression of ATOH1 in Development of Barrett's Esophagus in Rats

Abstract

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules involved in post-transcriptional gene regulation by RNA interference. They are critical regulators in many biologic functions, including gastrointestinal development and immune mediated diseases. There is currently nothing known regarding miRNA-regulated gene expression in Eosinophilic Esophagitis (EoE). EoE is a chronic allergen-mediated disorder of the esophagus characterized by symptoms of esophageal dysfunction and eosinophilic infiltration of the esophageal epithelium. Complications include significant morbidity from feeding aversion, food bolus impaction, esophageal stricture and spontaneous esophageal perforation. Several pathogenic pathways have been described in EoE, the majority of which relate to Th2 cellmediated activation of epithelial cell inflammatory signals, eosinophilic infiltration of the esophagus and epithelial damage. In light of the widespread function of miRNA, we hypothesize that miRNA expression is altered in EoE and contributes to disease pathogenesis. PATIENTS AND METHODS: Esophageal biopsies were collected from pediatric subjects at time of upper endoscopy. RNA was isolated from 6 subjects with EoE (≥20 eos/hpf, endoscopic appearance consistent with EoE, and upper GI symptoms) and 6 matched controls. The miRNA expression profile of each sample was assessed using a direct hybridization platform. The Significance Analysis of Microarrays was used to detect differences in gene expression based on criteria of false discovery rate 1.5. Alterations in miRNA levels were validated by direct quantitative PCR and validated in a larger cohort. RESULTS: Twelve miRNAs were identified to be up-regulated and 2 miRNA were down-regulated in EoE compared to controls. MiR-21 was one of the most highly up-regulated (4.3 fold change) and miR-375 was the most down-regulated (5.9 fold change). The results of the large-scale platform were confirmed by qPCR. Several of the identified EoE-associated miRNAs, including miR-21, are implicated in other Th2 mediated disorders including allergic asthma and psoriasis. Others are altered in other esophageal disease states, such as esophageal adenocarcinoma and squamous cell carcinoma. CONCLUSIONS: These data represent the first description of miRNA expression and gene regulation in EoE. Our findings may lead to new diagnostic tools and targeted therapies for EoE.