Phelan J J, MacCarthy F, Feighery R, O'Farrell N J, Lynam-Lennon N, Doyle B, O'Toole D, Ravi N, Reynolds J V, O'Sullivan J
Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
Cancer Lett. 2014 Nov 1;354(1):122-31. doi: 10.1016/j.canlet.2014.07.035. Epub 2014 Aug 10.
Contemporary clinical management of Barrett's oesophagus has highlighted the lack of accurate predictive markers of disease progression to oesophageal cancer. This study aims to examine alterations in mitochondrial energy metabolism profiles across the entire disease progression sequence in Barrett's oesophagus. An in-vitro model was used to screen 84 genes associated with mitochondrial energy metabolism. Three energy metabolism genes (ATP12A, COX4I2, COX8C) were significantly altered across the in-vitro Barrett's disease sequence. In-vivo validations across the Barrett's sequence demonstrated differential expression of these genes. Tissue microarrays demonstrated significant alterations in both epithelial and stromal oxidative phosphorylation (ATP5B and Hsp60) and glycolytic (PKM2 and GAPDH) protein markers across the in-vivo Barrett's sequence. Levels of ATP5B in sequential follow up surveillance biopsy material segregated Barrett's non progressors and progressors to HGD and cancer. Utilising the Seahorse XF24 flux analyser, in-vitro Barrett's and adenocarcinoma cells exhibited altered levels of various oxidative parameters. We show for the first time that mitochondrial energy metabolism is differentially altered across the metaplasia-dysplasia-adenocarcinoma sequence and that oxidative phosphorylation profiles have predictive value in segregating Barrett's non progressors and progressors to adenocarcinoma.
巴雷特食管的当代临床管理凸显了缺乏疾病进展为食管癌的准确预测标志物。本研究旨在检查巴雷特食管整个疾病进展过程中线粒体能量代谢谱的变化。使用体外模型筛选与线粒体能量代谢相关的84个基因。在体外巴雷特病进展过程中，三个能量代谢基因（ATP12A、COX4I2、COX8C）发生了显著变化。在巴雷特食管进展过程中的体内验证显示了这些基因的差异表达。组织芯片显示，在体内巴雷特食管进展过程中，上皮和基质氧化磷酸化（ATP5B和Hsp60）以及糖酵解（PKM2和GAPDH）蛋白标志物均有显著变化。在连续随访监测活检材料中，ATP5B水平区分了巴雷特食管无进展者和进展为高级别上皮内瘤变及癌症者。利用海马XF24通量分析仪，体外培养的巴雷特食管细胞和腺癌细胞的各种氧化参数水平发生了改变。我们首次表明，线粒体能量代谢在化生-发育异常-腺癌序列中存在差异改变，并且氧化磷酸化谱在区分巴雷特食管无进展者和进展为腺癌者方面具有预测价值。
