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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 the carcinogenic progression from squamous epithelium to Barrett's adenocarcinoma(A) T-UCRs significantly dysregulated in the Barrett's carcinogenic cascade (normal squamous epithelium [Sq] - Barrett's mucosa [BE] - low-grade intra-epithelial neoplasia [LG] - high-grade intra-epithelial neoplasia [HG] - Barrett's adenocarcinoma [BAc]) as assessed on microarray data. Rows represent individual genes; 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). The down-regulation of uc.214+ (B) and the up-regulation of uc.202- (C) were confirmed by qRT-PCR in a separate set of biopsy samples.
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Figure 5: T-UCR expression is altered in the carcinogenic progression from squamous epithelium to Barrett's adenocarcinoma(A) T-UCRs significantly dysregulated in the Barrett's carcinogenic cascade (normal squamous epithelium [Sq] - Barrett's mucosa [BE] - low-grade intra-epithelial neoplasia [LG] - high-grade intra-epithelial neoplasia [HG] - Barrett's adenocarcinoma [BAc]) as assessed on microarray data. Rows represent individual genes; 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). The down-regulation of uc.214+ (B) and the up-regulation of uc.202- (C) were confirmed by qRT-PCR in a separate set of biopsy samples.

Mentions: The analysis identified five T-UCRs that were differently expressed (p<0.001) in cases undergoing Barrett's carcinogenesis (Figure 5A). In particular, the signature included four T-UCRs (uc.58-, uc.202-, uc.207-, and uc.223-) with a higher expression and one (uc.214+) with a lower expression. Three of the Sq-BAc dysregulated T-UCRs (i.e. uc.202-, uc.214+ and uc.223) were shared with the progression signature from Sq to BAc (Figure 5A). QRT-PCR analyses for uc.214+ (Figure 5B) and uc.202- (Figure 5C) confirmed the microarray data.


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 the carcinogenic progression from squamous epithelium to Barrett's adenocarcinoma(A) T-UCRs significantly dysregulated in the Barrett's carcinogenic cascade (normal squamous epithelium [Sq] - Barrett's mucosa [BE] - low-grade intra-epithelial neoplasia [LG] - high-grade intra-epithelial neoplasia [HG] - Barrett's adenocarcinoma [BAc]) as assessed on microarray data. Rows represent individual genes; 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). The down-regulation of uc.214+ (B) and the up-regulation of uc.202- (C) were confirmed by qRT-PCR in a separate set of biopsy samples.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: T-UCR expression is altered in the carcinogenic progression from squamous epithelium to Barrett's adenocarcinoma(A) T-UCRs significantly dysregulated in the Barrett's carcinogenic cascade (normal squamous epithelium [Sq] - Barrett's mucosa [BE] - low-grade intra-epithelial neoplasia [LG] - high-grade intra-epithelial neoplasia [HG] - Barrett's adenocarcinoma [BAc]) as assessed on microarray data. Rows represent individual genes; 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). The down-regulation of uc.214+ (B) and the up-regulation of uc.202- (C) were confirmed by qRT-PCR in a separate set of biopsy samples.
Mentions: The analysis identified five T-UCRs that were differently expressed (p<0.001) in cases undergoing Barrett's carcinogenesis (Figure 5A). In particular, the signature included four T-UCRs (uc.58-, uc.202-, uc.207-, and uc.223-) with a higher expression and one (uc.214+) with a lower expression. Three of the Sq-BAc dysregulated T-UCRs (i.e. uc.202-, uc.214+ and uc.223) were shared with the progression signature from Sq to BAc (Figure 5A). QRT-PCR analyses for uc.214+ (Figure 5B) and uc.202- (Figure 5C) confirmed the microarray data.

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