Up-regulation of Activation-Induced Cytidine Deaminase Causes Genetic Aberrations at the CDKN2b-CDKN2a in Gastric Cancer
Up-regulation of Activation-Induced Cytidine Deaminase Causes Genetic Aberrations at the CDKN2b-CDKN2a in Gastric Cancer
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DOI：
10.1053/j.gastro.2010.07.010
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发表时间：
2010-12-01
期刊：
影响因子：
29.4
通讯作者：
Chiba, Tsutomu
中科院分区：
文献类型：
--
作者：
Matsumoto, Yuko;Marusawa, Hiroyuki;Chiba, Tsutomu
背景与目的：DNA/RNA 编辑酶激活诱导的胞苷脱氨酶 (AID) 具有诱变性，与人类肿瘤发生有关。胃上皮细胞幽门螺杆菌感染导致AID异常表达和体细胞基因突变。我们研究了 AID 是否会诱导胃上皮细胞中编码肿瘤相关蛋白的特定染色体位点发生遗传畸变。方法：检测表达活化 AID 的人胃上皮细胞系和来自 AID 转基因小鼠的胃细胞的 DNA 拷贝数变化和核苷酸变化。还分析了幽门螺杆菌感染小鼠胃细胞和幽门螺杆菌阳性患者胃组织（正常和肿瘤）的拷贝数畸变。结果：在人胃细胞中，异常的 AID 活性诱导了各个染色体位点的拷贝数变化。在AID转基因小鼠的AID表达细胞和胃粘膜中，抑癌基因CDKN2A和CDKN2B经常观察到点突变和拷贝数减少。口服幽门螺杆菌感染的野生型小鼠减少了 Cdkn2b-Cdkn2a 基因座的拷贝数，而在幽门螺杆菌感染的 AID 缺陷小鼠的胃粘膜中没有观察到这种变化。在人类样本中，与周围非癌区域相比，部分胃癌组织中 CDKN2A 和 CDKN2B 的相对拷贝数有所减少。结论：幽门螺杆菌感染导致AID异常表达，可能是胃上皮细胞亚显微缺失和体细胞突变积累的机制。 AID 介导的基因毒性作用似乎经常发生在 CDKN2b-CDKN2a 基因座上，并导致胃粘膜的恶性转化。
BACKGROUND & AIMS: The DNA/RNA editing enzyme activation-induced cytidine deaminase (AID) is mutagenic and has been implicated in human tumorigenesis. Helicobacter pylori infection of gastric epithelial cells leads to aberrant expression of AID and somatic gene mutations. We investigated whether AID induces genetic aberrations at specific chromosomal loci that encode tumor-related proteins in gastric epithelial cells. METHODS: Human gastric epithelial cell lines that express activated AID and gastric cells from AID transgenic mice were examined for DNA copy number changes and nucleotide alterations. Copy number aberrations in stomach cells of H pylori-infected mice and gastric tissues (normal and tumor) from H pylori-positive patients were also analyzed. RESULTS: In human gastric cells, aberrant AID activity induced copy number changes at various chromosomal loci. In AID-expressing cells and gastric mucosa of AID transgenic mice, point mutations and reductions in copy number were observed frequently in the tumor suppressor genes CDKN2A and CDKN2B. Oral infection of wild-type mice with H pylori reduced the copy number of the Cdkn2b-Cdkn2a locus, whereas no such changes were observed in the gastric mucosa of H pylori-infected AID-deficient mice. In human samples, the relative copy numbers of CDKN2A and CDKN2B were reduced in a subset of gastric cancer tissues compared with the surrounding noncancerous region. CONCLUSIONS: H pylori infection leads to aberrant expression of AID and might be a mechanism of the accumulation of submicroscopic deletions and somatic mutations in gastric epithelial cells. AID-mediated genotoxic effects appear to occur frequently at the CDKN2b-CDKN2a locus and contribute to malignant transformation of the gastric mucosa.