The Barrett’s Antigen Anterior Gradient-2 Silences the p53 Transcriptional Response to DNA Damage

Abstract

The esophageal epithelium is subject to damage from bile acid reflux that promotes normal tissue injury resulting in the development of Barrett's epithelium. There is a selection pressure for mutating p53 in this preneoplastic epithelium, thus identifying a physiologically relevant model for discovering novel regulators of the p53 pathway. Proteomic technologies were used to identify such p53 regulatory factors by identifying proteins that were overexpressed in Barrett's epithelium. A very abundant polypeptide selectively expressed in Barrett's epithelium was identified as anterior gradient-2. Immunochemical methods confirmed that anterior gradient-2 is universally up-regulated in Barrett's epithelium, relative to normal squamous tissue derived from the same patient. Cancer development is a multistep process involving sequential mutation in oncogenes and tumor suppressor genes that give selective advantage to the evolving cancer cells. The major clinical models that are giving novel molecular mechanistic insight into the multistep evolution of human neoplasia include colorectal and esophageal cancer. Colorectal cancer progression is perhaps the most well-characterized model whereby cancer development evolves through histopathological stages termed dysplasia, adenoma, and carcinoma, which can eventually metastasize. Classic molecular studies in colorectal cancer have indicated that RAS and APC mutations occur earlier in this progression sequence, while p53 mutations occur relatively later (1). Additional modifying factors include genome instability, (2), DNA methylation (3), and associated epigenetic changes in the expression of regulatory genes that can have profound effects on cancer incidence (4).Esophageal adenocarcinoma cancer progression also proceeds through a set of morphological intermediates termed metaplasia and dysplasia, which are collectively called Barrett's esophagus or Barrett's epithelium (5, 6). Barrett's epithelium is thought to develop as an adaptive response following exposure to gastric and duodenal contents refluxed into the esophagus. Barrett's epithelium is a premalignant lesion, and although the progression from Barrett's cell types to adenocarcinoma is not inevitable, the risk is estimated at an increase of 30-to 125-fold as compared with the normal population (7-9) The incidence of Barrett's epithelium has dramatically increased over the last decade; however, more alarming is the parallel increase in adenocarcinoma of the esophagus over a similar period of time (10). Barrett's epithelium being hyperproliferative is believed to be a fertile field for malignant transformation, and such early premalignant lesions produce biological and genetic heterogeneity as seen in previous studies by p53 mutations, aneuploidy, and abnormal methylation resulting in stepwise changes in differentiation, proliferation, and apoptosis (11). However, the environmental, genetic, and metabolic factors that regulate stress responses in normal and Barrett's epithelium, as well as the associated transformation o...

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The protein disulfide isomerase AGR2 is essential for production of intestinal mucus

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The pro-metastatic protein anterior gradient-2 predicts poor prognosis in tamoxifen-treated breast cancers

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