title: Activation-induced cytidine deaminase is dispensable for virus-mediated liver and skin tumor development in mouse models.
abstract: Activation-induced cytidine deaminase (AID) not only promotes immune diversity by initiating somatic hypermutation and class switch recombination in immunoglobulin genes but also provokes genomic instability by introducing translocations and mutations into non-immunoglobulin genes. To test whether AID is essential for virus-induced tumor development, we used two transgenic tumor models: mice expressing hepatitis C virus (HCV) core proteins (HCV-Tg), driven by the hepatitis B virus promoter, and mice expressing human papillomavirus type 8 proteins (HPV8-Tg), driven by the Keratin 14 promoter. Both strains were analyzed in the absence and presence of AID by crossing each with AID (-/-) mice. There was no difference in the liver tumor frequency between the HCV-Tg/AID (+/+) and HCV-Tg/AID (-/-) mice at 20 months of age although the AID (+/+) mice showed more severe histological findings and increased cytokine expression. Furthermore, a low level of AID transcript was detected in the HCV-Tg/AID (+/+) liver tissue that was not derived from hepatocytes themselves but from intra-hepatic immune cells. Although AID may not be the direct cause of HCV-induced oncogenesis, AID expressed in B cells, not in hepatocytes, may prolong steatosis and cause increased lymphocyte infiltration into HCV core protein-induced liver lesions. Similarly, there was no difference in the time course of skin tumor development between the HPV8-Tg/AID (-/-) and HPV8-Tg/AID (+/+) groups. In conclusion, AID does not appear to be required for tumor development in the two virus-induced tumor mouse models tested although AID expressed in infiltrating B cells may promote inflammatory reactions in HCV core protein-induced liver pathogenesis.
authors.affiliation: Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Tung
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Chikuma
authors.affiliation: Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hiai
authors.affiliation: Shiga Medical Center Research Institute, Moriyama, Shiga 524-8524, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kinoshita
authors.affiliation: Department of Infection Control and Prevention, University of Tokyo, Bunkyo, Tokyo 113-8655, Japan.
authors.forename: Kyoji
authors.initials: K
authors.lastname: Moriya
authors.affiliation: Department of Gastroenterology, University of Tokyo, Bunkyo, Tokyo 113-8655, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.affiliation: Institute of Virology and Center for Molecular Medicine Cologne, University of Cologne, Cologne D-50931, Germany.
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Marcuzzi
authors.affiliation: Institute of Virology and Center for Molecular Medicine Cologne, University of Cologne, Cologne D-50931, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Pfister
authors.affiliation: Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan honjo@mfour.med.kyoto-u.ac.jp.
authors.forename: Tasuku
authors.initials: T
authors.lastname: Honjo
authors.affiliation: Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003564:Cytidine Deaminase / Q000172:deficiency / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006526:Hepatitis C / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010212:Papilloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D027383:Papillomaviridae / Q000472:pathogenicity; D030361:Papillomavirus Infections / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D012333:RNA, Messenger; D014758:Viral Core Proteins; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
keywords: hepatitis C virus; human papillomavirus type 8