title: Stratification of Hepatocellular Carcinoma Patients Based on Acetate Utilization.
abstract: Hepatocellular carcinoma (HCC) is a deadly form of liver cancer that is increasingly prevalent. We analyzed global gene expression profiling of 361 HCC tumors and 49 adjacent noncancerous liver samples by means of combinatorial network-based analysis. We investigated the correlation between transcriptome and proteome of HCC and reconstructed a functional genome-scale metabolic model (GEM) for HCC. We identified fundamental metabolic processes required for cell proliferation using the network centric view provided by the GEM. Our analysis revealed tight regulation of fatty acid biosynthesis (FAB) and highly significant deregulation of fatty acid oxidation in HCC. We predicted mitochondrial acetate as an emerging substrate for FAB through upregulation of mitochondrial acetyl-CoA synthetase (ACSS1) in HCC. We analyzed heterogeneous expression of ACSS1 and ACSS2 between HCC patients stratified by high and low ACSS1 and ACSS2 expression and revealed that ACSS1 is associated with tumor growth and malignancy under hypoxic conditions in human HCC.
authors.affiliation: Department of Biology and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden.
authors.forename: Elias
authors.initials: E
authors.lastname: Björnson
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Bani
authors.initials: B
authors.lastname: Mukhopadhyay
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Asplund
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Nusa
authors.initials: N
authors.lastname: Pristovsek
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Resat
authors.initials: R
authors.lastname: Cinar
authors.affiliation: Department of Molecular and Clinical Medicine, the Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory, University of Gothenburg, 413 45 Gothenburg, Sweden; Cardiology Department, Sahlgrenska University Hospital, 416 50 Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, 88100 Catanzaro, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Romeo
authors.affiliation: Department of Proteomics, KTH-Royal Institute of Technology, 106 91 Stockholm, Sweden; Science for Life Laboratory, KTH-Royal Institute of Technology, 171 21 Stockholm, Sweden.
authors.forename: Mathias
authors.initials: M
authors.lastname: Uhlen
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: George
authors.initials: G
authors.lastname: Kunos
authors.affiliation: Department of Biology and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden; Science for Life Laboratory, KTH-Royal Institute of Technology, 171 21 Stockholm, Sweden.
authors.forename: Jens
authors.initials: J
authors.lastname: Nielsen
authors.affiliation: Department of Biology and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden; Science for Life Laboratory, KTH-Royal Institute of Technology, 171 21 Stockholm, Sweden. Electronic address: adilm@scilifelab.se.
authors.forename: Adil
authors.initials: A
authors.lastname: Mardinoglu
mesh_terms: D000106:Acetate-CoA Ligase / Q000235:genetics / Q000378:metabolism; D000085:Acetates / Q000378:metabolism*; D000368:Aged; D000465:Algorithms; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005227:Fatty Acids / Q000096:biosynthesis; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000085:Acetates; D005227:Fatty Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; C000595379:ACSS2 protein, human; D000106:Acetate-CoA Ligase
keywords: ACSS1; ACSS2; acetate; genome-scale metabolic models; hepatocellular carcinoma; proteome; transcriptome