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.