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Expression of activation-induced cytidine deaminase in human hepatocytes via NF-κB signaling

Oncogene volume 26, pages 5587–5595 (2007)Cite this article

Abstract

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-α stimulation in cultured human hepatocytes. The proinflammatory cytokine-mediated expression of AID is achieved by IκB kinase-dependent nuclear factor (NF)-κB signaling pathways. Hepatitis C virus, one of the leading causes of hepatocellular carcinoma (HCC), enhanced AID expression via NF-κB 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.

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Acknowledgements

We are grateful to Y Ueda for his useful suggestions and critical reading of the paper, Y Matsumoto for helpful advice and T Kou for help with the analyses on Tg mice. This study was supported by a grant in aid for Scientific Research (15209024, 16790378 and 17002015) from the Japan Society for the Promotion of Science (JSPS).

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Y Endo, H Marusawa, T Morisawa, T Sakurai & T Chiba

  2. Evolutionary Medicine, Shiga Medical Center Research Institute, Moriyama, Japan

    K Kinoshita

  3. Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    I-M Okazaki & T Honjo

  4. Department of Viral Oncology, Laboratory of Human Tumor Viruses, Institute for Virus Research, Kyoto University, Kyoto, Japan

    K Watashi & K Shimotohno

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  1. Y Endo
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Correspondence to T Chiba.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Endo, Y., Marusawa, H., Kinoshita, K. et al. Expression of activation-induced cytidine deaminase in human hepatocytes via NF-κB signaling. Oncogene 26, 5587–5595 (2007). https://doi.org/10.1038/sj.onc.1210344

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