Alteration of protein expression and spliceosome pathway activity during Barrett’s carcinogenesis

Background Barrett’s esophagus (BE) is a known precursor lesion and the strongest risk factor for esophageal adenocarcinoma (EAC), a common and lethal type of cancer. Prediction of risk, the basis for efficient intervention, is commonly solely based on histologic examination. This approach is challe...

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Bibliographic Details
Published in:	Journal of gastroenterology Vol. 56; no. 9; pp. 791 - 807
Main Authors:	Stingl, Christoph, Bureo Gonzalez, Angela, Güzel, Coşkun, Phoa, Kai Yi Nadine, Doukas, Michail, Breimer, Gerben Eise, Meijer, Sybren Lodewijk, Bergman, Jacques Johannes, Luider, Theo Marten
Format:	Journal Article
Language:	English
Published:	Singapore Springer Singapore 01-09-2021 Springer Springer Nature B.V
Subjects:	Abdominal Surgery Adenocarcinoma Analysis Barrett Esophagus - genetics Barrett Esophagus - pathology Carcinogenesis Colorectal Surgery Development and progression Diagnosis Disease Progression DNA damage DNA repair Endoscopic Mucosal Resection - methods Endoscopic Mucosal Resection - statistics & numerical data Esophageal cancer Esophagus Gastroenterology Gene Expression - physiology Genetic research Health aspects Hepatology Humans Immunohistochemistry Mass spectrometry Mass spectroscopy Medicine Medicine & Public Health MicroRNAs - metabolism MSH6 protein Mucosa Netherlands Original Article—Alimentary Tract Original —Alimentary Tract Patients Proteins Quantitation Risk factors RNA transport Spliceosomes - genetics Spliceosomes - physiology Surgical Oncology Netherlands Adenocarcinoma Barrett’s esophagus Laser capture microdissection Mass spectrometry Proteomics
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Summary:	Background Barrett’s esophagus (BE) is a known precursor lesion and the strongest risk factor for esophageal adenocarcinoma (EAC), a common and lethal type of cancer. Prediction of risk, the basis for efficient intervention, is commonly solely based on histologic examination. This approach is challenged by problems such as inter-observer variability in the face of the high heterogeneity of dysplastic tissue. Molecular markers might offer an additional way to understand the carcinogenesis and improve the diagnosis—and eventually treatment. In this study, we probed significant proteomic changes during dysplastic progression from BE into EAC. Methods During endoscopic mucosa resection, epithelial and stromal tissue samples were collected by laser capture microdissection from 10 patients with normal BE and 13 patients with high-grade dysplastic/EAC. Samples were analyzed by mass spectrometry-based proteomic analysis. Expressed proteins were determined by label-free quantitation, and gene set enrichment was used to find differentially expressed pathways. The results were validated by immunohistochemistry for two selected key proteins (MSH6 and XPO5). Results Comparing dysplastic/EAC to non-dysplastic BE, we found in equal volumes of epithelial tissue an overall up-regulation in terms of protein abundance and diversity, and determined a set of 226 differentially expressed proteins. Significantly higher expressions of MSH6 and XPO5 were validated orthogonally and confirmed by immunohistochemistry. Conclusions Our results demonstrate that disease-related proteomic alterations can be determined by analyzing minute amounts of cell-type-specific collected tissue. Further analysis indicated that alterations of certain pathways associated with carcinogenesis, such as micro-RNA trafficking, DNA damage repair, and spliceosome activity, exist in dysplastic/EAC.
ISSN:	0944-1174 1435-5922
DOI:	10.1007/s00535-021-01802-2