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 alpha-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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging / genetics
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Aging / metabolism
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Alkaline Phosphatase / genetics
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Alkaline Phosphatase / metabolism*
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Animals
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Antigens, Differentiation / genetics
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Antigens, Differentiation / metabolism
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B-Lymphocytes / metabolism
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B-Lymphocytes / pathology
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism*
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Carcinoma, Hepatocellular / pathology
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Cytidine Deaminase / genetics
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Cytidine Deaminase / metabolism*
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Disease Models, Animal
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Embryo, Mammalian / metabolism
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Embryo, Mammalian / pathology
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Gene Expression Regulation, Neoplastic* / genetics
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Genome, Human / genetics
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Hepatitis / genetics
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Hepatitis / metabolism
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Hepatitis / pathology
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Humans
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Liver / metabolism
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Liver / pathology
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism*
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Liver Neoplasms / pathology
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Mice
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Mice, Transgenic
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Organ Specificity / genetics
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Sequence Deletion / genetics
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Somatic Hypermutation, Immunoglobulin / genetics
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Stem Cells / metabolism
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Stem Cells / pathology
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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alpha-Fetoproteins / genetics
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alpha-Fetoproteins / metabolism
Substances
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Antigens, Differentiation
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Tumor Suppressor Protein p53
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alpha-Fetoproteins
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Alkaline Phosphatase
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AICDA (activation-induced cytidine deaminase)
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Cytidine Deaminase