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Int. J. Mol. Sci. 2017, 18(2), 434; doi:10.3390/ijms18020434

Proteome Characteristics of Non-Alcoholic Steatohepatitis Liver Tissue and Associated Hepatocellular Carcinomas

1
Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Asahi-machi 1-4-3, Abeno-ku, Osaka 545-8585, Japan
2
Department of Biochemistry, Saint Petersburg State University, Saint Petersburg 199034, Russia
3
Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
4
Department of Environmental Oncology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Joseph V. Moxon
Received: 12 December 2016 / Revised: 24 January 2017 / Accepted: 9 February 2017 / Published: 17 February 2017
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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. View Full-Text
Keywords: nonalcoholic steatohepatitis (NASH); hepatocellular carcinoma; biopsy; PPARs; β-catenin; cytokeratins 8/18; NRIP1; oxidative stress nonalcoholic steatohepatitis (NASH); hepatocellular carcinoma; biopsy; PPARs; β-catenin; cytokeratins 8/18; NRIP1; oxidative stress
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Kakehashi, A.; Stefanov, V.E.; Ishii, N.; Okuno, T.; Fujii, H.; Kawai, K.; Kawada, N.; Wanibuchi, H. Proteome Characteristics of Non-Alcoholic Steatohepatitis Liver Tissue and Associated Hepatocellular Carcinomas. Int. J. Mol. Sci. 2017, 18, 434.

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