title: The senescent hepatocyte gene signature in chronic liver disease.
abstract: Hepatocyte senescence is associated closely with fibrosis stage and an adverse outcome in chronic liver disease, but it is uncertain whether there is a causal relation with clinical manifestations of chronic liver disease, which was the subject of this study of the senescent hepatocyte gene signature. Senescence was induced in HepG2 cells using sub-lethal concentrations of H2O2. Gene expression of control and senescent HepG2 cells were studied. Comparison was made with patients with cirrhosis and three public microarray datasets. H2O2-treated HepG2 cells demonstrated characteristic cellular senescence. There was differential expression of 354 genes in senescence. Up-regulated genes in HepG2 senescence were also up regulated in patients with cirrhosis. The senescent hepatocyte gene signature distinguished liver disease from normal by unsupervised clustering in the public chronic liver disease microarray datasets, with enrichment of the senescence gene signature in all three datasets. The senescent hepatocyte gene signature included changes in cell cycle regulation, morphology, inflammation, signal transduction, metabolism and stellate cell activation, which alongside impaired synthetic function in senescence in vitro were consistent with manifestations of clinical liver disease, suggesting a close relation between hepatocyte senescence and manifestations of chronic liver disease including fibrosis and impaired synthetic function.
authors.affiliation: Division of Gastroenterology & Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Aloysious
authors.initials: A
authors.lastname: Aravinthan
authors.affiliation: Cancer Research UK Cambridge Institute, Cambridge, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Shannon
authors.affiliation: Division of Gastroenterology & Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK; Foundation for Liver Research, Institute of Hepatology, London, UK.
authors.forename: Judith
authors.initials: J
authors.lastname: Heaney
authors.affiliation: Division of Gastroenterology & Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK; Cancer Research UK Cambridge Institute, Cambridge, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hoare
authors.affiliation: Division of Gastroenterology & Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK; Royal Free London NHS Foundation Trust, London, UK.
authors.forename: Aileen
authors.initials: A
authors.lastname: Marshall
authors.affiliation: Division of Gastroenterology & Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK. Electronic address: gja1000@doctors.org.uk.
authors.forename: Graeme J M
authors.initials: GJ
authors.lastname: Alexander
mesh_terms: D017209:Apoptosis / Q000235:genetics; D016022:Case-Control Studies; D002453:Cell Cycle / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics* / Q000502:physiology*; D002908:Chronic Disease; D016207:Cytokines / Q000235:genetics; D015536:Down-Regulation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008103:Liver Cirrhosis / Q000235:genetics / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics* / Q000473:pathology*; D018384:Oxidative Stress; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation
chemical_list: D016207:Cytokines
keywords: Chronic liver disease; Hepatocyte senescence; Senescence gene signature