title: Differential expression of mitochondrial energy metabolism profiles across the metaplasia-dysplasia-adenocarcinoma disease sequence in Barrett's oesophagus.
abstract: 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.
authors.affiliation: Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
authors.forename: J J
authors.initials: JJ
authors.lastname: Phelan
authors.affiliation: Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
authors.forename: F
authors.initials: F
authors.lastname: MacCarthy
authors.affiliation: Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
authors.forename: R
authors.initials: R
authors.lastname: Feighery
authors.affiliation: Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
authors.forename: N J
authors.initials: NJ
authors.lastname: O'Farrell
authors.affiliation: Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
authors.forename: N
authors.initials: N
authors.lastname: Lynam-Lennon
authors.affiliation: Department of Pathology, St. James's Hospital, Dublin, Ireland.
authors.forename: B
authors.initials: B
authors.lastname: Doyle
authors.affiliation: Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
authors.forename: D
authors.initials: D
authors.lastname: O'Toole
authors.affiliation: Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
authors.forename: N
authors.initials: N
authors.lastname: Ravi
authors.affiliation: Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
authors.forename: J V
authors.initials: JV
authors.lastname: Reynolds
authors.affiliation: Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland. Electronic address: osullij4@tcd.ie.
authors.forename: J
authors.initials: J
authors.lastname: O'Sullivan
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D001471:Barrett Esophagus / Q000378:metabolism* / Q000473:pathology; D001706:Biopsy; D045744:Cell Line, Tumor; D018450:Disease Progression; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D006801:Humans; D008679:Metaplasia / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010100:Oxygen / Q000737:chemistry; D010766:Phosphorylation
chemical_list: C539675:COX4I2 protein, human; C477826:COX8C protein, human; D003576:Electron Transport Complex IV; C088641:ATP12A protein, human; D017506:H(+)-K(+)-Exchanging ATPase; D010100:Oxygen
keywords: Barrett's metaplasia; Glycolysis; Mitochondrial dysfunction; Mitochondrial energy metabolism; Oesophageal cancer; Oxidative phosphorylation