Telomere Shortening in Barrett's Esophagus | Oncotarget
Channel: Oncotarget
Date: 2022-07-15

Oncotarget published this trending research paper on February 14, 2022 in Volume 13, entitled, "Telomere shortening accelerates tumor initiation in the L2-IL1B mouse model of Barrett esophagus and emerges as a possible biomarker" by researchers from II Medizinische Klinik, Technische Universität München, Munich, Germany; Department of Medicine, Columbia University Irving Medical Center, New York, NY; Klinik für Innere Medizin II, Universitätsklinikum Freiburg, Freiburg, Germany.

DOI - https://doi.org/10.18632/oncotarget.28198

Correspondence to - Michael Quante - michael.quante@uniklinik-freiburg.de

Abstract

Barrett’s esophagus (BE) is a precursor of the esophageal adenocarcinoma (EAC). BE- development and its progression to cancer is associated with gastroesophageal reflux disease. However, there is currently no molecular risk prediction model that accurately identifies patients at high risk for EAC. Here, we investigated the impact of shortened telomeres in a mouse model for Barrett esophagus (L2-IL1B). The L2-IL1B mouse model is characterized by IL-1β-mediated inflammation, which leads to a Barrett-like metaplasia in the transition zone between the squamous forestomach and glandular cardia/stomach. Telomere shortening was achieved by mTERC knockout. In the second generation (G2) of mTERC knockout L2-IL1B.mTERC−/− G2 mice exhibited telomere dysfunction with significantly shorter telomeres as measured by qFISH compared to L2-IL1B mice, correlating with stronger DNA damage in the form of phosphorylation of H2AX (γH2AX). Macroscopically, tumor area along the squamocolumnar junction (SCJ) was increased in L2-IL1B.mTERC−/− G2 mice, along with increased histopathological dysplasia. In vitro studies indicated increased organoid formation capacity in BE tissue from L2-IL1B.mTERC−/− G2 mice. In addition, pilot studies of human BE-, dysplasia- and EAC tissue samples confirmed that BE epithelial cells with or without dysplasia (LGD) had shorter telomeres compared to gastric cardia tissue. Of note, differentiated goblet cells retained longer telomeres than columnar lined BE epithelium. In conclusion, our studies suggest that shortened telomeres are functionally important for tumor development in a mouse model of BE and are associated with proliferating columnar epithelium in human BE. We propose that shortened telomeres should be evaluated further as a possible biomarker of cancer risk in BE patients.

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Keywords - Barrett's esophagus, telomere shortening, esophageal cancer, risk factor, TERT/TERC

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