Transcribed ultraconserved noncoding RNAs (T-UCR) are involved in Barrett’s esophagus carcinogenesis
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Matteo Fassan1,2,3, Luigi Dall’Olmo4, Marco Galasso5, Chiara Braconi6, Marco Pizzi1, Stefano Realdon4, Stefano Volinia3,5, Nicola Valeri6, Pierluigi Gasparini3, Raffaele Baffa7,*, Rhonda F. Souza8, Caterina Vicentini9, Edoardo D’Angelo2, Jan Bornschein10, Gerard J. Nuovo3, Giovanni Zaninotto2, Carlo M. Croce3 and Massimo Rugge1,4
1 Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy
2 Department of Surgical Oncology and Gastroenterological Sciences (DiSCOG), University of Padua, Padua, Italy
3 Comprehensive Cancer Center, Ohio State University, Columbus, OH
4 Istituto Oncologico Veneto - IOV-IRCCS, Padua, Italy
5 Department of Morphology and Embryology; University of Ferrara, Ferrara, Italy
6 Institute of Cancer Research, London, UK
7 Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
8 Department of Medicine, University of Texas Southwestern Medical Center & VA North Texas Health Care System, Dallas, TX
9 ARC-NET Research Centre, University of Verona, Verona, Italy
10 Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany
* Current address: Sanofi, Cambridge, MA, USA
Massimo Rugge, email:
Keywords: T-UCRs; Barrett’s esophagus; Barrett’s carcinogenesis; expression signature
Received: June 24, 2014 Accepted: July 22, 2014 Published: July 23, 2014
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.
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