title: Role of oxidative stress in hepatocarcinogenesis induced by hepatitis C virus.
abstract: Hepatitis C virus (HCV) easily establishes chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). During the progression of HCV infections, reactive oxygen species (ROS) are generated, and these ROS then induce significant DNA damage. The role of ROS in the pathogenesis of HCV infection is still not fully understood. Recently, we found that HCV induced the expression of 3β-hydroxysterol Δ24-reductase (DHCR24). We also found that a HCV responsive region is present in the 5'-flanking genomic promoter region of DHCR24 and the HCV responsive region was characterized as (-167/-140). Moreover, the transcription factor Sp1 was found to bind to this region in response to oxidative stress under the regulation of ataxia telangiectasia mutated (ATM) kinase. Overexpression of DHCR24 impaired p53 activity by suppression of acetylation and increased interaction with MDM2. This impairment of p53 suppressed the hydrogen peroxide-induced apoptotic response in hepatocytes. Thus, a target of oxidative stress in HCV infection is DHCR24 through Sp1, which suppresses apoptotic responses and increases tumorigenicity.
authors.affiliation: Department of Animal Hygiene, Transboundary Animal Diseases Center, Joint Faculty of Veterinary Medicine Kagoshima University, 1-21-24 Korimoto, Kagoshima 890-0065, Japan. kkohara@agri.kagoshima-u.ac.jp
authors.forename: Kyoko
authors.initials: K
authors.lastname: Tsukiyama-Kohara
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism*; D002472:Cell Transformation, Viral; D015972:Gene Expression Regulation, Neoplastic; D016174:Hepacivirus / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000150:complications*; D054884:Host-Pathogen Interactions; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics; D018384:Oxidative Stress; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D016159:Tumor Suppressor Protein p53; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human