Barrett食管(BE)是食管腺癌(EAC)的前兆。BE-发展及其进展为癌症与胃食管反流病有关。然而,目前尚无分子风险预测模型能够准确识别EAC高危患者.这里,我们研究了Barrett食管(L2-IL1B)小鼠模型中端粒缩短的影响.L2-IL1B小鼠模型的特征是IL-1β介导的炎症,这导致鳞状前胃和腺体贲门/胃之间的过渡区出现巴雷特样化生。端粒缩短是通过mTERC敲除实现的。在第二代(G2)mTERC敲除L2-IL1B。mTERC-/-G2小鼠表现出端粒功能障碍,与L2-IL1B小鼠相比,qFISH测量的端粒明显较短,与H2AX(γH2AX)磷酸化形式的更强DNA损伤相关。宏观上,在L2-IL1B中,沿着鳞状纤维结(SCJ)的肿瘤面积增加。mTERC-/-G2小鼠,伴随着组织病理学发育不良的增加。体外研究表明,来自L2-IL1B的BE组织中的类器官形成能力增加。mTERC-/-G2小鼠。此外,人类BE的试点研究-,异型增生和EAC组织样本证实,与胃贲门组织相比,有或没有异型增生(LGD)的BE上皮细胞端粒较短.值得注意的是,分化的杯状细胞保留的端粒比柱状排列的BE上皮更长。总之,我们的研究表明,端粒缩短对BE小鼠模型中肿瘤的发展具有重要的功能,并且与人BE中柱状上皮的增殖有关。我们建议应进一步评估缩短的端粒作为BE患者癌症风险的可能生物标志物。
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.