Oncotarget

Research Papers:

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

Matteo Fassan, Luigi Dall’Olmo, Marco Galasso, Chiara Braconi, Marco Pizzi, Stefano Realdon, Stefano Volinia, Nicola Valeri, Pierluigi Gasparini, Raffaele Baffa, Rhonda F. Souza, Caterina Vicentini, Edoardo D’Angelo, Jan Bornschein, Gerard J. Nuovo, Giovanni Zaninotto, Carlo M. Croce, Massimo Rugge _

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Oncotarget. 2014; 5:7162-7171. https://doi.org/10.18632/oncotarget.2249

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Abstract

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

Correspondence:

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

Abstract

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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