Expression of activation-induced cytidine deaminase in human hepatocytes during hepatocarcinogenesis
Expression of activation-induced cytidine deaminase in human hepatocytes during hepatocarcinogenesis
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DOI：
10.1002/ijc.22292
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发表时间：
2007-02-01
影响因子：
6.4
通讯作者：
Chiba, Tsutomu
中科院分区：
文献类型：
--
作者：
Kou, Tadayuki;Marusawa, Hiroyuki;Chiba, Tsutomu
活化诱导的胞苷脱氨酶（AID）在活化的B细胞中起着基因组突变剂的作用，并且AID的不适当表达与人类B细胞恶性肿瘤的免疫病理表型有关。值得注意的是，我们发现过表达AID的转基因小鼠发生肺腺癌和肝细胞癌（HCC），这表明AID的异位表达也可以导致上皮组织中的肿瘤发生。为了研究AID在人类HCC发展中的参与，我们分析了51例接受原发性HCC切除术患者肝组织中AID表达及其与p53基因突变频率的相关性。在培养的人肝细胞中研究AID的特异性表达、细胞因子刺激的诱导和诱变活性。在正常肝脏中仅检测到痕量的AID转录物;然而，内源性AID在HCC和具有潜在慢性肝炎或肝硬化的周围非癌肝组织中均显著上调（p < 0.05）。大多数具有内源性AID上调的潜在慢性炎症的肝组织已经包含p53基因的多种遗传变化。在肝癌细胞系和培养的人原代肝细胞中，AID的表达基本上由TGF-β刺激诱导。AID在肝细胞中的异常激活导致p53基因中多种遗传改变的积累。我们的研究结果表明，AID的异常表达在人类肝细胞中观察到几种病理设置，包括慢性肝病和HCC，这可能会增加遗传易感性突变导致肝癌发生。(c)2006 Wiley-Liss，Inc.
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 p53 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 p53 gene. In both hepatoma cell lines and cultured human primary hepatocytes, the expression of AID was substantially induced by TGF-beta stimulation. Aberrant activation of AID in hepatocytes resulted in accumulation of multiple genetic alterations in the p53 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. (c) 2006 Wiley-Liss, Inc.