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Expression of activation‐induced cytidine deaminase in human hepatocytes during hepatocarcinogenesis
Author(s) -
Kou Tadayuki,
Marusawa Hiroyuki,
Kinoshita Kazuo,
Endo Yoko,
Okazaki Ilmi,
Ueda Yoshihide,
Kodama Yuzo,
Haga Hironori,
Ikai Iwao,
Chiba Tsutomu
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22292
Subject(s) - cytidine deaminase , biology , downregulation and upregulation , cancer research , carcinogenesis , activation induced (cytidine) deaminase , hepatocyte , hepatocellular carcinoma , cirrhosis , gene expression , microbiology and biotechnology , gene , immunology , medicine , in vitro , b cell , somatic hypermutation , genetics , antibody
Abstract Activation‐induced cytidine deaminase (AID) plays a role as a genome mutator in activated B cells, and inappropriate expression of AID has been implicated in the immunopathological phenotype of human B‐cell malignancies. Notably, we found that the transgenic mice overexpressing AID developed lung adenocarcinoma and hepatocellular carcinoma (HCC), suggesting that ectopic expression of AID can lead to tumorigenesis in epithelial tissues as well. To examine the involvement of AID in the development of human HCC, we analyzed the AID expression and its correlation with mutation frequencies of the p 53 gene in liver tissues from 51 patients who underwent resection of primary HCCs. The specific expression, inducibility by cytokine stimulation and mutagenic activity of AID were investigated in cultured human hepatocytes. Only trace amounts of AID transcripts were detected in the normal liver; however, endogenous AID was significantly upregulated in both HCC and surrounding noncancerous liver tissues with underlying chronic hepatitis or liver cirrhosis ( p < 0.05). Most liver tissues with underlying chronic inflammation with endogenous AID upregulation already contained multiple genetic changes in the p 53 gene. In both hepatoma cell lines and cultured human primary hepatocytes, the expression of AID was substantially induced by TGF‐β stimulation. Aberrant activation of AID in hepatocytes resulted in accumulation of multiple genetic alterations in the p 53 gene. Our findings suggest that the aberrant expression of AID is observed in human hepatocytes with several pathological settings, including chronic liver disease and HCC, which might enhance the genetic susceptibility to mutagenesis leading to hepatocarcinogenesis. © 2006 Wiley‐Liss, Inc.