title: Proteome Characteristics of Non-Alcoholic Steatohepatitis Liver Tissue and Associated Hepatocellular Carcinomas.
abstract: To uncover mechanisms of nonalcoholic steatohepatitis (NASH) associated hepatocarcinogenesis, we compared the proteomes of human NASH-associated liver biopsies, resected hepatocellular carcinomas (HCCs) and HCCs of HCV⁺ patients with normal liver tissue of patients with gastrointestinal tumor metastasis, in formalin-fixed paraffin-embedded samples obtained after surgery in our hospital during the period from 2006 to 2011. In addition, proteome analysis of liver tumors in male STAM NASH-model mice was performed. Similar changes in the proteome spectrum such as overexpression of enzymes involved in lipid, cholesterol and bile acid biosynthesis and examples associated with suppression of fatty acid oxidation and catabolism, alcohol metabolism, mitochondrial function as well as low expression levels of cytokeratins 8 and 18 were observed in both human NASH biopsies and NASH HCCs, but not HCV⁺ HCCs. Alterations in downstream protein expression pointed to significant activation of transforming growth factor β, SMAD family member 3, β-catenin, Nrf2, SREBP-LXRα and nuclear receptor-interacting protein 1 (NRIP1), and inhibition of PPARs and p53 in human NASH biopsies and/or HCCs, suggesting their involvement in accumulation of lipids, development of fibrosis, oxidative stress, cell proliferation and suppression of apoptosis in NASH hepatocarcinogenesis. In STAM mice, PPARs inhibition was not obvious, while expression of cytokeratins 8 and 18 was elevated, indicative of essential differences between human and mouse NASH pathogenesis.
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Asahi-machi 1-4-3, Abeno-ku, Osaka 545-8585, Japan. anna@med.osaka-cu.ac.jp.
authors.forename: Anna
authors.initials: A
authors.lastname: Kakehashi
authors.affiliation: Department of Biochemistry, Saint Petersburg State University, Saint Petersburg 199034, Russia. vastef@mail.ru.
authors.forename: Vasily E
authors.initials: VE
authors.lastname: Stefanov
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Asahi-machi 1-4-3, Abeno-ku, Osaka 545-8585, Japan. m1159070@med.osaka-cu.ac.jp.
authors.forename: Naomi
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Asahi-machi 1-4-3, Abeno-ku, Osaka 545-8585, Japan. m2026860@med.osaka-cu.ac.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Okuno
authors.affiliation: Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan. rolahideki@med.osaka-cu.ac.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
authors.affiliation: Department of Environmental Oncology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan. kkawai@med.uoeh-u.ac.jp.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Kawai
authors.affiliation: Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan. kawadanori@med.osaka-cu.ac.jp.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Kawada
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Asahi-machi 1-4-3, Abeno-ku, Osaka 545-8585, Japan. wani@med.osaka-cu.ac.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Wanibuchi
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis; D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D049109:Cell Proliferation; D005260:Female; D016174:Hepacivirus / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D018384:Oxidative Stress; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D020543:Proteome; D051153:Wnt Proteins; D051176:beta Catenin
keywords: NRIP1; PPARs; biopsy; cytokeratins 8/18; hepatocellular carcinoma; nonalcoholic steatohepatitis (NASH); oxidative stress; β-catenin