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

Christoph Stingl*, Angela Bureo Gonzalez, Coşkun Güzel, Kai Yi Nadine Phoa, Michail Doukas, Gerben Eise Breimer, Sybren Lodewijk Meijer, Jacques Johannes Bergman, Theo Marten Luider

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)791-807
Number of pages17
JournalJournal of Gastroenterology
Volume56
Issue number9
DOIs
Publication statusPublished - 5 Jul 2021

Bibliographical note

Funding Information:
We thank Ko Hagoort for critical reading of the manuscript and the Erasmus MC Cancer Computational Biology Center (CCBC) for providing their IT resources and sharing their software.

Publisher Copyright:
© 2021, The Author(s).

Fingerprint

Dive into the research topics of 'Alteration of protein expression and spliceosome pathway activity during Barrett’s carcinogenesis'. Together they form a unique fingerprint.

Cite this