RRC ID 11769
Author Takai A, Toyoshima T, Uemura M, Kitawaki Y, Marusawa H, Hiai H, Yamada S, Okazaki IM, Honjo T, Chiba T, Kinoshita K.
Title A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations.
Journal Oncogene
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.
Volume 28(4)
Pages 469-78
Published 2009-1-29
DOI 10.1038/onc.2008.415
PII onc2008415
PMID 18997814
MeSH Aging / genetics Aging / metabolism Alkaline Phosphatase / genetics Alkaline Phosphatase / metabolism* Animals Antigens, Differentiation / genetics Antigens, Differentiation / metabolism B-Lymphocytes / metabolism B-Lymphocytes / pathology Carcinoma, Hepatocellular / genetics Carcinoma, Hepatocellular / metabolism* Carcinoma, Hepatocellular / pathology Cytidine Deaminase / genetics Cytidine Deaminase / metabolism* Disease Models, Animal Embryo, Mammalian / metabolism Embryo, Mammalian / pathology Gene Expression Regulation, Neoplastic* / genetics Genome, Human / genetics Hepatitis / genetics Hepatitis / metabolism Hepatitis / pathology Humans Liver / metabolism Liver / pathology Liver Neoplasms / genetics Liver Neoplasms / metabolism* Liver Neoplasms / pathology Mice Mice, Transgenic Organ Specificity / genetics Sequence Deletion / genetics Somatic Hypermutation, Immunoglobulin / genetics Stem Cells / metabolism Stem Cells / pathology Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / metabolism* alpha-Fetoproteins / genetics alpha-Fetoproteins / metabolism
IF 6.634
Times Cited 41