Dataset Information

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

ABSTRACT:

Introduction

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.

Methods

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.

Results

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 β-catenin were detected in nondysplastic BE. Nuclear active β-catenin and TOPflash activity were increased in CP-A and OE33 cells compared with squamous cells. Wnt3a-mediated β-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.

Conclusions

Despite the absence of robust nuclear accumulation, β-catenin is transcriptionally active in nondysplastic BE. Dkk1 overexpression regulates β-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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Publications

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

Similar Datasets

Project description:Background & aimsBarrett'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.MethodsWe 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.ResultsWe 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.ConclusionsIn 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.

Dataset Information

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

Introduction

Methods

Results

Conclusions

Publications

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

Similar Datasets

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