p16 hypermethylation during gastric carcinogenesis of Wistar rats by N-methyl-N′-nitro-N-nitrosoguanidine
p16 hypermethylation during gastric carcinogenesis of Wistar rats by N-methyl-N′-nitro-N-nitrosoguanidine
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DOI：
10.1016/s1383-5718(02)00288-7
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发表时间：
2003-02-05
影响因子：
1.9
通讯作者：
Deng, DJ
中科院分区：
文献类型：
--
作者：
Bai, H;Gu, LK;Deng, DJ
抑癌基因p16的甲基化失活是包括胃癌在内的多种肿瘤中的常见事件。本研究的目的是探讨p16基因甲基化是否是N-甲基-N '-硝基-N-亚硝基胍（MNNG）诱导胃癌发生的早期和频繁事件。在Wistar大鼠的多步骤胃癌发生过程中，p16高甲基化的频率和时间进行了分析，在各种显微解剖胃病变。采用甲基化特异性PCR和免疫组化方法检测P16基因甲基化状态和p16蛋白的表达。结果显示，p16基因甲基化频率与胃粘膜病变程度呈正相关。p16基因甲基化在正常胃黏膜、慢性萎缩性胃炎、异型增生、胃腺瘤和胃癌中的阳性率分别为2.7%、16.7%、37.5%、67.4%和85.2%。远端胃上皮p16甲基化高于近端胃上皮。p16蛋白在15 p16未甲基化的胃上皮中均有表达，而在12 p16甲基化的胃上皮中无表达。这些结果表明，CpG岛甲基化可能是导致大鼠胃中p16沉默的原因，并且是其积累最终导致胃癌发生的早期事件。(C)2002 Elsevier Science B. V.保留所有权利。
Inactivation of the tumor suppressor gene, p16 by CpG hypermethylation is a common event in various tumors including gastric carcinoma. The aim of this study is to investigate if p16 hypermethylation is an early and frequent event in gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The frequency and timing of p16 hypermethylation during the multistep gastric carcinogenesis in Wistar rats were analyzed in various microdissected gastric lesions. The P16 methylation status and the presence of p16 protein were analyzed by methylation-specific PCR and immunohistochemistry, respectively. Results showed that p16 methylation frequency was correlated with the severity of gastric pathologic lesions, positively. For instance, p16 methylation was found in 2.7% of normal gastric epithelium (n 36), 16.7% of chronic atrophy gastritis (n = 24), 37.5% of dysplasia (n = 24), 67.4% of gastric adenoma (n = 43), and 85.2% of gastric carcinoma (n = 27). The p16 methyliation in the distal stomach epithelium was higher than that in the proximal stomach. p16 protein was expressed in all of 15p16 unmethylated gastric epithelial samples, but not expressed in all of 12p16 methylated samples. These results suggest that CpG island hypermethylation may account for the silencing of p16 in rat stomach and is an early event whose accumulation will finally lead to gastric carcinogenesis. (C) 2002 Elsevier Science B.V. All rights reserved.