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

Fassan M, Dall'Olmo L, Galasso M, Braconi C, Pizzi M, Realdon S, Volinia S, Valeri N, Gasparini P, Baffa R, Souza RF, Vicentini C, D'Angelo E, Bornschein J, Nuovo GJ, Zaninotto G, Croce CM, Rugge M - Oncotarget (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy. Department of Surgical Oncology and Gastroenterological Sciences (DiSCOG), University of Padua, Padua, Italy. Comprehensive Cancer Center, Ohio State University, Columbus, OH.

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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T-UCR expression is altered in Barrett's esophageal adenocarcinomaT-UCRs significantly dysregulated (p<0.001) in Barrett's adenocarcinoma (BAc) by comparison with normal squamous esophageal epithelium (Sq, A), or Barrett's mucosa (BE, B). Rows represent individual T-UCRs; columns represent individual tissue samples. Pseudo-colors indicate transcript levels below, equating to, or above the mean (green, black, and red, respectively). The scale represents the intensity of gene expression (log2 scale ranges between -3 and 3). (C) ISH analysis confirmed that uc.329+ was significantly down-regulated in BAc. Sq showed moderate uc.329+ expression in basal and suprabasal cell compartments (right, upper panel); which was much decreased in the BAc. Scale bars, 200 and 100 μm; original magnifications, 5x and 20x.
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Figure 4: T-UCR expression is altered in Barrett's esophageal adenocarcinomaT-UCRs significantly dysregulated (p<0.001) in Barrett's adenocarcinoma (BAc) by comparison with normal squamous esophageal epithelium (Sq, A), or Barrett's mucosa (BE, B). Rows represent individual T-UCRs; columns represent individual tissue samples. Pseudo-colors indicate transcript levels below, equating to, or above the mean (green, black, and red, respectively). The scale represents the intensity of gene expression (log2 scale ranges between -3 and 3). (C) ISH analysis confirmed that uc.329+ was significantly down-regulated in BAc. Sq showed moderate uc.329+ expression in basal and suprabasal cell compartments (right, upper panel); which was much decreased in the BAc. Scale bars, 200 and 100 μm; original magnifications, 5x and 20x.

Mentions: Different T-UCR expression profiles were identified when Sq and BE were compared with BAc (Figure 4A-C). In particular, seven T-UCRs were found dysregulated in BAc by comparison with Sq (uc.202-, uc.223-, and uc.269- were up-regulated, and uc.214+, uc.328+, uc.329+, and uc.356+ were down-regulated) and two were dysregulated in BAc by comparison with BE (uc.204+ and uc.389+ were down-regulated). ISH confirmed the down-regulation of uc.329+ in BAc in 4/5 cases (Figure 4B). The uc.329+ expression was mainly cytoplasmic. A moderate expression was observed in the basal and suprabasal cell compartments of all five Sq specimens.


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

Fassan M, Dall'Olmo L, Galasso M, Braconi C, Pizzi M, Realdon S, Volinia S, Valeri N, Gasparini P, Baffa R, Souza RF, Vicentini C, D'Angelo E, Bornschein J, Nuovo GJ, Zaninotto G, Croce CM, Rugge M - Oncotarget (2014)

T-UCR expression is altered in Barrett's esophageal adenocarcinomaT-UCRs significantly dysregulated (p<0.001) in Barrett's adenocarcinoma (BAc) by comparison with normal squamous esophageal epithelium (Sq, A), or Barrett's mucosa (BE, B). Rows represent individual T-UCRs; columns represent individual tissue samples. Pseudo-colors indicate transcript levels below, equating to, or above the mean (green, black, and red, respectively). The scale represents the intensity of gene expression (log2 scale ranges between -3 and 3). (C) ISH analysis confirmed that uc.329+ was significantly down-regulated in BAc. Sq showed moderate uc.329+ expression in basal and suprabasal cell compartments (right, upper panel); which was much decreased in the BAc. Scale bars, 200 and 100 μm; original magnifications, 5x and 20x.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196192&req=5

Figure 4: T-UCR expression is altered in Barrett's esophageal adenocarcinomaT-UCRs significantly dysregulated (p<0.001) in Barrett's adenocarcinoma (BAc) by comparison with normal squamous esophageal epithelium (Sq, A), or Barrett's mucosa (BE, B). Rows represent individual T-UCRs; columns represent individual tissue samples. Pseudo-colors indicate transcript levels below, equating to, or above the mean (green, black, and red, respectively). The scale represents the intensity of gene expression (log2 scale ranges between -3 and 3). (C) ISH analysis confirmed that uc.329+ was significantly down-regulated in BAc. Sq showed moderate uc.329+ expression in basal and suprabasal cell compartments (right, upper panel); which was much decreased in the BAc. Scale bars, 200 and 100 μm; original magnifications, 5x and 20x.
Mentions: Different T-UCR expression profiles were identified when Sq and BE were compared with BAc (Figure 4A-C). In particular, seven T-UCRs were found dysregulated in BAc by comparison with Sq (uc.202-, uc.223-, and uc.269- were up-regulated, and uc.214+, uc.328+, uc.329+, and uc.356+ were down-regulated) and two were dysregulated in BAc by comparison with BE (uc.204+ and uc.389+ were down-regulated). ISH confirmed the down-regulation of uc.329+ in BAc in 4/5 cases (Figure 4B). The uc.329+ expression was mainly cytoplasmic. A moderate expression was observed in the basal and suprabasal cell compartments of all five Sq specimens.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy. Department of Surgical Oncology and Gastroenterological Sciences (DiSCOG), University of Padua, Padua, Italy. Comprehensive Cancer Center, Ohio State University, Columbus, OH.

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.

Show MeSH
Related in: MedlinePlus