A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations
| Autor: | Tasuku Honjo, Atsushi Takai, Tsutomu Chiba, Hiroshi Hiai, Kazuo Kinoshita, Munehiro Uemura, Il-mi Okazaki, Hiroyuki Marusawa, Yoko Kitawaki, Takae Toyoshima, S. Yamada |
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| Rok vydání: | 2008 |
| Předmět: |
Genetically modified mouse
Cancer Research Aging Carcinoma Hepatocellular Somatic hypermutation Mice Transgenic Biology medicine.disease_cause Stem cell marker Hepatitis Mice Germline mutation Cytidine Deaminase Genetics medicine Activation-induced (cytidine) deaminase Animals Humans Molecular Biology Sequence Deletion B-Lymphocytes Genome Human Stem Cells Liver Neoplasms Cytidine deaminase Alkaline Phosphatase Embryo Mammalian Molecular biology Antigens Differentiation digestive system diseases Gene Expression Regulation Neoplastic Disease Models Animal Liver Organ Specificity biology.protein Somatic Hypermutation Immunoglobulin alpha-Fetoproteins Stem cell Tumor Suppressor Protein p53 Carcinogenesis |
| Zdroj: | Oncogene. 28(4) |
| ISSN: | 1476-5594 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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