A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations.
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.
Takai
A
A
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Toyoshima
T
T
Uemura
M
M
Kitawaki
Y
Y
Marusawa
H
H
Hiai
H
H
Yamada
S
S
Okazaki
I M
IM
Honjo
T
T
Chiba
T
T
Kinoshita
K
K
D000375:Aging / Q000235:genetics / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D006505:Hepatitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000509:alpha-Fetoproteins / Q000235:genetics / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D000943:Antigens, Differentiation; D016159:Tumor Suppressor Protein p53; D000509:alpha-Fetoproteins; D000469:Alkaline Phosphatase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase