Expression of activation-induced cytidine deaminase in human hepatocytes via NF-κB signaling
Expression of activation-induced cytidine deaminase in human hepatocytes via NF-κB signaling
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DOI：
10.1038/sj.onc.1210344
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发表时间：
2007-08-01
期刊：
影响因子：
8
通讯作者：
Chiba, T.
中科院分区：
文献类型：
--
作者：
Endo, Y.;Marusawa, H.;Chiba, T.
激活诱导胞苷脱氨酶（AID）参与免疫球蛋白基因的体细胞DNA改变以扩增免疫多样性。AID在小鼠体内的组成性表达可引起包括淋巴组织和肺部在内的多种器官的肿瘤，这一事实表明，AID对多种肿瘤相关基因的异常编辑活性在致癌过程中发挥了重要作用。然而，在生理条件下，AID的表达仅限于活化的B细胞。我们在此证明异位AID表达是对培养的人肝细胞中肿瘤坏死因子- α刺激的反应。促炎细胞因子介导的AID表达是通过I κ B激酶依赖核因子(NF)- κ B信号通路实现的。丙型肝炎病毒是导致肝细胞癌（HCC）的主要原因之一，通过表达病毒核心蛋白NF-kappa B激活AID表达。在肝癌源性细胞中，AID的异常表达导致c-myc和pim1基因的遗传改变积累，这表明AID的不适当表达作为DNA突变体，增强了人肝细胞对突变的遗传易感性。我们目前的研究结果表明AID的不适当表达是由促炎细胞因子刺激引起的，并且可能在肝脏炎症和HCC的发展之间提供了联系。
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 I kappa B kinase-dependent nuclear factor (NF)-kappa B signaling pathways. Hepatitis C virus, one of the leading causes of hepatocellular carcinoma (HCC), enhanced AID expression via NF-kappa B 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.