title: Hepatic inflammation facilitates transcription-associated mutagenesis via AID activity and enhances liver tumorigenesis.
abstract: Chronic inflammation triggers the aberrant expression of a DNA mutator enzyme, activation-induced cytidine deaminase (AID), and contributes to tumorigenesis through the accumulation of genetic aberrations. To gain further insight into the inflammation-mediated genotoxic events required for carcinogenesis, we examined the role of chronic inflammation in the emergence of genetic aberrations in the liver with constitutive AID expression. Treatment with thioacetamide (TAA) at low-dose concentrations caused minimal hepatic inflammation in both wild-type (WT) and AID transgenic (Tg) mice. None of the WT mice with low-dose TAA administration or AID Tg mice without hepatic inflammation developed cancers in their liver tissues over the 6 month study period. In contrast, all the AID Tg mice with TAA treatment developed multiple macroscopic hepatocellular carcinomas during the same observation period. Whole exome sequencing and additional deep-sequencing analyses revealed the enhanced accumulation of somatic mutations in various genes, including dual specificity phosphatase 6 (Dusp6), early growth response 1 (Egr1) and inhibitor of DNA binding 2 (Id2), which are putative tumor suppressors, in AID-expressing liver with TAA-mediated hepatic inflammation. Microarray and quantitative reverse transcription-polymerase chain reaction analyses showed the transcriptional upregulation of various genes including Dusp6, Egr1 and Id2 under hepatic inflammatory conditions. Together, these findings suggest that inflammation-mediated transcriptional upregulation of target genes, including putative tumor suppressor genes, enhances the opportunity for inflamed cells to acquire somatic mutations and contributes to the acceleration of tumorigenesis in the inflamed liver tissues.
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Nishijima
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Atsuyuki
authors.initials: A
authors.lastname: Ikeda
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Eso
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan maru@kuhp.kyoto-u.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Marusawa
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics; D051766:Early Growth Response Protein 1 / Q000235:genetics; D005786:Gene Expression Regulation; D006521:Hepatitis, Chronic / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016296:Mutagenesis; D009154:Mutation; D013853:Thioacetamide / Q000008:administration & dosage; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D013853:Thioacetamide; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase