RESUMO
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.
Assuntos
Fosfatase Alcalina/metabolismo , Carcinoma Hepatocelular/metabolismo , Citidina Desaminase/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Envelhecimento/genética , Envelhecimento/metabolismo , Fosfatase Alcalina/genética , Animais , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/metabolismo , Linfócitos B/metabolismo , Linfócitos B/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Citidina Desaminase/genética , Modelos Animais de Doenças , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Regulação Neoplásica da Expressão Gênica/genética , Genoma Humano/genética , Hepatite/genética , Hepatite/metabolismo , Hepatite/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Transgênicos , Especificidade de Órgãos/genética , Deleção de Sequência/genética , Hipermutação Somática de Imunoglobulina/genética , Células-Tronco/metabolismo , Células-Tronco/patologia , Proteína Supressora de Tumor p53/genética , alfa-Fetoproteínas/genética , alfa-Fetoproteínas/metabolismoRESUMO
Activation-induced cytidine deaminase (AID) is involved in somatic DNA alterations of the immunoglobulin gene for amplification of immune diversity. The fact that constitutive expression of AID in mice causes tumors in various organs, including lymphoid tissues and lungs, suggests the important role of the aberrant editing activity of AID on various tumor-related genes for carcinogenesis. AID expression, however, is restricted to activated B cells under physiological conditions. We demonstrate here that ectopic AID expression is induced in response to tumor necrosis factor-alpha stimulation in cultured human hepatocytes. The proinflammatory cytokine-mediated expression of AID is achieved by IkappaB kinase-dependent nuclear factor (NF)-kappaB signaling pathways. Hepatitis C virus, one of the leading causes of hepatocellular carcinoma (HCC), enhanced AID expression via NF-kappaB activation through expression of viral core protein. The aberrant expression of AID in hepatoma-derived cells resulted in accumulation of genetic alterations in the c-myc and pim1 genes, suggesting that inappropriate expression of AID acts as a DNA mutator that enhances the genetic susceptibility to mutagenesis in human hepatocytes. Our current findings indicate that the inappropriate expression of AID is induced by proinflammatory cytokine stimulation and may provide the link between hepatic inflammation and the development of HCC.