Abstract
Activation-induced cytidine deaminase (AID), the only enzyme that is known to be able to induce mutations in the human genome, is required for somatic hypermutation and class-switch recombination in B lymphocytes. Recently, we showed that AID is implicated in the pathogenesis of human cancers including hepatitis C virus (HCV)-induced human hepatocellular carcinoma (HCC). In this study, we established a new AID transgenic mouse model (TNAP-AID) in which AID is expressed in cells producing tissue-nonspecific alkaline phosphatase (TNAP), which is a marker of primordial germ cells and immature stem cells, including ES cells. High expression of TNAP was found in the liver of the embryos and adults of TNAP-AID mice. HCC developed in 27% of these mice at the age of approximately 90 weeks. The HCC that developed in TNAP-AID mice expressed α-fetoprotein and had deleterious mutations in the tumour suppressor gene Trp53, some of which corresponded to those found in human cancer. In conclusion, TNAP-AID is a mouse model that spontaneously develops HCC, sharing genetic and phenotypic features with human HCC, which develops in the inflamed liver as a result of the accumulation of genetic changes.
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Acknowledgements
We thank Dr Andras Nagy for his generous gift of TNAP-Cre mice, Dr Takashi Shinohara for suggesting the choice of the Cre mouse strain, Dr Yoshinobu Toda for the preparation of tissue sections and Dr Masayuki Tsuji for technical help with the immunohistochemical analyses. We also thank Dr Sidonia Fagarasan for critical reading of the manuscript and discussions. This study was supported by Grant-in-Aid for Scientific Research (17013042 and 18390122) and the Takeda Science Foundation.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)
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Takai, A., Toyoshima, T., Uemura, M. et al. A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations. Oncogene 28, 469–478 (2009). https://doi.org/10.1038/onc.2008.415
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DOI: https://doi.org/10.1038/onc.2008.415
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