Transcribed ultraconserved noncoding RNAs (T-UCR) are involved in Barrett's esophagus carcinogenesis

• Published in: Oncotarget 2014-08, Vol.5 (16), p.7162-7171
• Main Authors: Fassan, Matteo, Dall'Olmo, Luigi, Galasso, Marco, Braconi, Chiara, Pizzi, Marco, Realdon, Stefano, Volinia, Stefano, Valeri, Nicola, Gasparini, Pierluigi, Baffa, Raffaele, Souza, Rhonda F, Vicentini, Caterina, D'Angelo, Edoardo, Bornschein, Jan, Nuovo, Gerard J, Zaninotto, Giovanni, Croce, Carlo M, Rugge, Massimo
• Format: Article
• Language: English
• Subjects: Aged; Animals; Barrett Esophagus - genetics; Barrett Esophagus - pathology; Carcinogenesis; Cell Transformation, Neoplastic - genetics; Disease Models, Animal; Disease Progression; Female; Humans; Male; Mice; Middle Aged; Rats; Rats, Wistar; Research Paper; RNA, Untranslated - genetics; Transcription, Genetic
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.2249

Barrett's esophagus (BE) involves a metaplastic replacement of native esophageal squamous epithelium (Sq) by columnar-intestinalized mucosa, and it is the main risk factor for Barrett-related adenocarcinoma (BAc). Ultra-conserved regions (UCRs) are a class non-coding sequences that are conserved in humans, mice and rats. More than 90% of UCRs are transcribed (T-UCRs) in normal tissues, and are altered at transcriptional level in tumorigenesis. To identify the T-UCR profiles that are dysregulated in Barrett's mucosa transformation, microarray analysis was performed on a discovery set of 51 macro-dissected samples obtained from 14 long-segment BE patients. Results were validated in an independent series of esophageal biopsy/surgery specimens and in two murine models of Barrett's esophagus (i.e. esophagogastric-duodenal anastomosis). Progression from normal to BE to adenocarcinoma was each associated with specific and mutually exclusive T-UCR signatures that included up-regulation of uc.58-, uc.202-, uc.207-, and uc.223- and down-regulation of uc.214+. A 9 T-UCR signature characterized BE versus Sq (with the down-regulation of uc.161-, uc.165-, and uc.327-, and the up-regulation of uc.153-, uc.158-, uc.206-, uc.274-, uc.472-, and uc.473-). Analogous BE-specific T-UCR profiles were shared by human and murine lesions. This study is the first demonstration of a role for T-UCRs in the transformation of Barrett's mucosa.