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.
Highlights
Non-alcoholic fatty liver disease (NAFLD), which has become a very common disease with the prevailing increase in obesity across the world, is generally considered to feature two stages—fatty liver (FL) (non-alcoholic fatty liver (NAFL)) followed in some cases by non-alcoholic steatohepatitis (NASH)
nonalcoholic steatohepatitis (NASH) is widely known as a liver disease with the potential to cause cirrhosis, and hepatocellular carcinoma (HCC), recent evidence has suggested that NAFLD may directly promote hepatic carcinogenesis independent of cirrhosis [3]
In all NASH-associated biopsies and HCCs, we observed significant elevation of numerous extracellular matrix and cytoskeleton proteins, the majority of them being downstream of transforming growth factor β (TGF-β), including different types of collagens, fibronectin (FN), intermediate filament vimentin (VIM), β actin-like protein 2 (ACTB2), myosin 9 (MYH9), tropomyosin α-4 chain (TPMA4), tubulin α-1C chain (TUBA1C), moesin (MSN), lumican (LUM) and others (Table 1)
Summary
Non-alcoholic fatty liver disease (NAFLD), which has become a very common disease with the prevailing increase in obesity across the world, is generally considered to feature two stages—fatty liver (FL) (non-alcoholic fatty liver (NAFL)) followed in some cases by non-alcoholic steatohepatitis (NASH). While liver cirrhosis secondary to hepatitis C infection is still the main cause of liver cancer and the most common indication for liver transplantation in the world, the prevalence of NAFLD and NASH-related cirrhosis and HCC will become an increasingly major health care problem in the future. Several studies have suggested that increased apoptosis of hepatocytes and angiogenesis have important roles in progression from simple FL to NASH, and correlate with disease severity and hepatic fibrosis [9,10]. Results of liquid chromatography and tandem mass spectrometry (LC-Ms/Ms) and Ingenuity Pathway analysis (IPA) of NASH-associated human biopsies in a high fibrosis stage and resected HCCs were compared with protein spectra of HCCs of hepatitis C virus (HCV)-positive (HCV+) patients and normal-appearing liver tissue from cases with metastases from gastrointestinal cancers. A mouse NASH HCC model was employed for comparison of human and mouse NASH-related changes in the proteome, upstream regulators, molecular functions and signaling pathways
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