Expression of activation-induced cytidine deaminase in human hepatocytes via NF-kappaB signaling.
Expression of activation-induced cytidine deaminase in human hepatocytes via NF-kappaB signaling.
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发表时间：
2007
期刊：
影响因子：
8
通讯作者：
Y. Endo;H. Marusawa;K. Kinoshita;T. Morisawa;T. Sakurai;I-M Okazaki;K. Watashi;K. Shimotohno;T. Honjo;T. Chiba
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作者：
Y. Endo;H. Marusawa;K. Kinoshita;T. Morisawa;T. Sakurai;I-M Okazaki;K. Watashi;K. Shimotohno;T. Honjo;T. Chiba
激活诱导型胞苷脱氨酶(AID)参与免疫球蛋白基因体细胞DNA的改变，以扩大免疫多样性。AID在小鼠体内的结构性表达可导致包括淋巴组织和肺在内的多种器官的肿瘤，这一事实表明AID在多种肿瘤相关基因上的异常编辑活性在致癌中起着重要作用。然而，在生理条件下，AID的表达仅限于激活的B细胞。我们在这里证明了在培养的人肝细胞中，肿瘤坏死因子-α刺激诱导了异位AID的表达。促炎症细胞因子介导的AID表达是通过IkappaB激酶依赖的核因子(NF)-kappaB信号通路实现的。丙型肝炎病毒是导致肝细胞癌的主要原因之一，它通过表达病毒核心蛋白来激活核因子-kappaB，从而增强艾滋病病毒的表达。AID在肝癌细胞中的异常表达导致c-myc和pim1基因的遗传改变积累，提示AID的不适当表达是一种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诱导的，并可能在肝脏炎症和肝细胞癌的发生发展之间提供联系。
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 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.