Abstract
The precursor metaplastic mucosal lesion that predisposes for esophageal adenocarcinoma is Barrett's esophagus. Because the signal transduction events that occur in Barrett's esophagus are poorly understood, this study aimed at generating a comprehensive description of cellular kinase activity in Barrett's esophagus, normal squamous esophagus, and gastric cardia to gain more insight into the pathogenesis of Barrett's esophagus. Peptide arrays, exhibiting 1,176 specific consensus sequences for protein kinases, were used to produce a global analysis of cellular kinase activity in biopsies of Barrett's esophagus, and results were compared with the neighboring cardia and squamous epithelia. Several differences in kinase activity using immunoblot analysis and enzyme activity assays were validated in biopsies of 27 Barrett's esophagus patients. Three unique kinome profiles are described and compared. We identified cascades of activated kinases showing that mitogen-activated protein kinase and epidermal growth factor receptor activity are both significantly altered in Barrett's esophagus compared with squamous and gastric cardia epithelia. Another novel finding is that the glycolysis pathway is significantly up-regulated in Barrett's esophagus, which is illustrated by an up-regulated pyruvate kinase activity. Here, the unique kinome profile of Barrett's esophagus is made available as a comprehensive database. Several signaling pathways are revealed as specifically expressed in Barrett's esophagus when compared with the adjacent normal epithelia. These unique findings provide novel insight in the pathogenesis of Barrett's esophagus that will ultimately help to resolve the increasing problem of Barrett's esophagus and prevention of esophageal adenocarcinoma.
Highlights
Barrett’s esophagus is widely recognized as a premalignant condition in which the normal squamous mucosa of the distal esophagus is replaced by a metaplastic mucosa, defined as an incompletely differentiated intestinal type of epithelium [1,2,3].Note: Supplementary data for this article are available at Cancer Research Online.I2006 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-06-1370Barrett’s esophagus is thought to be a complication of long standing gastroesophageal reflux disease (GERD) and can be found in 6% to 12% of patients with GERD [4, 5]
Normal squamous epithelium was biopsied at least 2 cm proximal of the Barrett’s segment, and gastric cardia was taken within 2 cm below the gastroesophageal junction
The results show a strong increase in glycolytic metabolism in Barrett’s esophagus compared with cardia epithelium, which was associated with down-regulated signaling through the insulin receptor and its downstream mediators phosphatidylinositol 3-kinase, protein kinase B, and GSK3 (Fig. 3B)
Summary
Barrett’s esophagus is widely recognized as a premalignant condition in which the normal squamous mucosa of the distal esophagus is replaced by a metaplastic mucosa, defined as an incompletely differentiated intestinal type of epithelium [1,2,3].Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).I2006 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-06-1370Barrett’s esophagus is thought to be a complication of long standing gastroesophageal reflux disease (GERD) and can be found in 6% to 12% of patients with GERD [4, 5]. Barrett’s esophagus is further associated with the highly malignant esophageal adenocarcinoma with an estimated annual incidence of f0.5% [6,7,8]. The phenotypic changes during the development of Barrett’s esophagus have been described in several studies [12,13,14,15]. Microarray and other gene expression profile studies have been done showing that, at the gene expression level, Barrett’s esophagus has strong similarities with the anatomic surrounding epithelia [16, 17]. At the level of cellular functions and processes, the pathophysiology of Barrett’s esophagus is hardly understood
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