Dataset Information

Wnt/?-Catenin Signaling Activation beyond Robust Nuclear ?-Catenin Accumulation in Nondysplastic Barrett's Esophagus: Regulation via Dickkopf-1.

ABSTRACT: Wnt/?-catenin signaling activation has been reported only during the late steps of Barrett's esophagus (BE) neoplastic progression, but not in BE metaplasia, based on the absence of nuclear ?-catenin. However, ?-catenin transcriptional activity has been recorded in absence of robust nuclear accumulation. Thus, we aimed to investigate the Wnt/?-catenin signaling in nondysplastic BE.Esophageal tissues from healthy and BE patients without dysplasia were analyzed for Wnt target gene expression by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry. Esophageal squamous (EPC1-& EPC2-hTERT), BE metaplastic (CP-A), and adenocarcinoma (OE33) cell lines were characterized for Wnt activation by qRT-PCR, Western blot, and luciferase assay. Wnt activity regulation was examined by using recombinant Wnt3a and Dickkopf-1 (Dkk1) as well as Dkk1 short interfering RNA.Wnt target genes (AXIN2, c-MYC, Cyclin D1, Dkk1) and Wnt3a were significantly upregulated in nondysplastic BE compared with squamous mucosa. Elevated levels of dephosphorylated ?-catenin were detected in nondysplastic BE. Nuclear active ?-catenin and TOPflash activity were increased in CP-A and OE33 cells compared with squamous cells. Wnt3a-mediated ?-catenin signaling activation was abolished by Dkk1 in CP-A cells. TOPFlash activity was elevated following Dkk1 silencing in CP-A but not in OE33 cells. Dysplastic and esophageal adenocarcinoma tissues demonstrated further Dkk1 and AXIN2 overexpression.Despite the absence of robust nuclear accumulation, ?-catenin is transcriptionally active in nondysplastic BE. Dkk1 overexpression regulates ?-catenin signaling in BE metaplastic but not in adenocarcinoma cells, suggesting that early perturbation of Dkk1-mediated signaling suppression may contribute to BE malignant transformation.

SUBMITTER: Lyros O

PROVIDER: S-EPMC4547437 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Wnt/β-Catenin Signaling Activation beyond Robust Nuclear β-Catenin Accumulation in Nondysplastic Barrett's Esophagus: Regulation via Dickkopf-1.

Lyros Orestis O Rafiee Parvaneh P Nie Linghui L Medda Rituparna R Jovanovic Nebojsa N Otterson Mary F MF Behmaram Behnaz B Gockel Ines I Mackinnon Alexander A Shaker Reza R

Neoplasia (New York, N.Y.) 20150701 7

<h4>Introduction</h4>Wnt/β-catenin signaling activation has been reported only during the late steps of Barrett's esophagus (BE) neoplastic progression, but not in BE metaplasia, based on the absence of nuclear β-catenin. However, β-catenin transcriptional activity has been recorded in absence of robust nuclear accumulation. Thus, we aimed to investigate the Wnt/β-catenin signaling in nondysplastic BE.<h4>Methods</h4>Esophageal tissues from healthy and BE patients without dysplasia were analyzed ...[more]

PMID: 26297437

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Project description:BACKGROUND & AIMS:Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Guidelines recommend that patients with nondysplastic BE (NDBE) undergo surveillance endoscopy every 3-5 years. We aimed to identify factors associated with surveillance endoscopy of patients with NDBE and identify trends in appropriate surveillance endoscopy of NDBE at a large tertiary care center. METHODS:We performed a retrospective analysis of data from a Barrett's Esophagus Registry, identifying patients with NDBE who underwent endoscopy in 2002 or later. We identified patients with NDBE and collected data on length of BE segment, esophageal lesions, demographic features, medications, histology findings, comorbidities, development of EAC, and dates of follow-up endoscopies. We defined appropriate surveillance as 3-5 years between 2nd and 3rd endoscopies, over-utilizers as patients who had less than 3 years between their 2nd and 3rd endoscopies, under-utilizers as patients who had more than 5 years between their 2nd and 3rd endoscopies; and never-surveilled as patients who never received a 2nd endoscopy. The primary outcomes were effects of patient factors, year, and referring providers on appropriateness of surveillance intervals. RESULTS:We identified 477 patients with NDBE. Only 15.9% had appropriate surveillance; 37.9% were over-utilizers 15.7% were under-utilizers and 30.4% were never surveilled. Patients were less likely to be over-surveilled if their primary care physician referred them for their 3rd endoscopy instead of a gastroenterologist (adjusted odds ratio, 0.51; 95% CI, 0.27-0.95). Male patients or those with an increased number of comorbidities were more likely to be under-surveilled or never-surveilled, whereas patients with long BE segment were more likely to be over-surveilled. CONCLUSIONS:In a retrospective analysis of data from a registry of patients with BE, we found that less than 16% receive appropriate surveillance for NDBE. A primary care provider in the same health system as the endoscopy clinic reduced risk of over-surveillance. This could reflect better coordination of care between specialists and primary care providers.

Project description:As the premalignant lesion of human esophageal adenocarcinoma (EAC), Barrett's esophagus (BE) is characterized by intestinal metaplasia in the normal esophagus (NE). Gene expression profiling with microarray and serial analysis of gene expression (SAGE) may help us understand the potential molecular mechanism of human BE.We analyzed three microarray datasets (two cDNA arrays and one oligonucleotide array) and one SAGE dataset with statistical tools, significance analysis of microarrays (SAM) and SAGE(Poisson), to identify individual genes differentially expressed in BE. Gene set enrichment analysis (GSEA) was used to identify a priori defined sets of genes that were differentially expressed. These gene sets were grouped according to either certain signaling pathways (GSEA curated), or the presence of consensus binding sequences of known transcription factors (GSEA motif). Immunohistochemical staining (IHC) was used to validate differential gene expression.Both SAM and SAGE(Poisson) identified 68 differentially expressed genes (55 BE genes and 13 NE genes) with an arbitrary cutoff ratio (> or =4-fold). With IHC on matched pairs of NE and BE tissues from 6 patients, these genes were grouped into 6 categories: category I (25 genes only expressed in BE), category II (5 genes only expressed in NE), category III (8 genes expressed more in BE than in NE), and category IV (2 genes expressed more in NE than in BE). Differential expression of the remaining genes was not confirmed by IHC either due to false discovery (category V), or lack of proper antibodies (category VI). Besides individual genes, the TGFbeta pathway and several transcription factors (CDX2, HNF1, and HNF4) were identified by GSEA as enriched pathways and motifs in BE. Apart from 9 target genes known to be up-regulated in BE, IHC staining confirmed up-regulation of 19 additional CDX1 and CDX2 target genes in BE.Our data suggested an important role of CDX1 and CDX2 in the development of BE. The IHC-confirmed gene list will lead to future studies on the molecular mechanism of BE.

Dataset Information

Wnt/?-Catenin Signaling Activation beyond Robust Nuclear ?-Catenin Accumulation in Nondysplastic Barrett's Esophagus: Regulation via Dickkopf-1.

Publications

Wnt/β-Catenin Signaling Activation beyond Robust Nuclear β-Catenin Accumulation in Nondysplastic Barrett's Esophagus: Regulation via Dickkopf-1.

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