Increased DNA methyltransferase 1 (DNMT1) protein expression correlates significantly with poorer tumor differentiation and frequent DNA hypermethylation of multiple CpG islands in gastric cancers
Increased DNA methyltransferase 1 (DNMT1) protein expression correlates significantly with poorer tumor differentiation and frequent DNA hypermethylation of multiple CpG islands in gastric cancers
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DOI：
10.1016/s0002-9440(10)63156-2
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发表时间：
2004-02-01
影响因子：
6
通讯作者：
Hirohashi, S
中科院分区：
文献类型：
--
作者：
Etoh, T;Kanai, Y;Hirohashi, S
我们评估了DNA甲基转移酶I（DNMT 1）蛋白表达异常在胃癌发生过程中的意义。应用免疫组化方法检测了134例胃癌及癌旁粘膜中DNMT 1、Muc 2、人胃粘蛋白、E-钙粘蛋白和增殖细胞核抗原的蛋白表达。通过甲基化特异性聚合酶链反应和联合亚硫酸氢盐限制性内切酶分析检测p16、人MutL同源物I（hMLH 1）、E-钙粘蛋白和血小板反应蛋白-1（THBS-1）基因的CpG岛以及肿瘤中甲基化（MINT）-1、-2、-12和-31克隆的DNA甲基化状态。原位杂交检测EB病毒感染。DNMT 1的核免疫反应性未检测到任何非癌上皮，除了在增殖区（阳性内部对照），但发现在97（72%）的胃癌。DNMT 1过表达与肿瘤分化程度相关（P < 0.001），但与肿瘤细胞表型（胃型与肠型）无关。胃癌组织中hMLH 1（P = 0.024）和THBS-1（P = 0.043）基因的CpG岛甲基化程度及CpG岛甲基化表型与胃癌组织中hMLH 1（P = 0.024）和THBS-1基因的CpG岛甲基化程度显著相关（P = 0.007）。E-cadherin表达的降低与肿瘤分化差（P = 0.002）、E-cadherin基因DNA甲基化（P < 0.001）和DNMT 1过表达（P = 0.014）显著相关。DNMT 1过表达也与EBV感染（胃癌发生的潜在致病因素）相关，但与癌细胞的增殖活性无关，如增殖细胞核抗原标记指数所示。这些结果表明，DNMT 1过表达可能不仅仅是癌细胞增殖活性增加的继发效应，而且可能与EBV感染和胃癌发生过程中的其他病因因素有关。此外，DNMT 1可能通过诱导多个CpG岛频繁的DNA超甲基化在低分化胃癌的发展中起重要作用。
We evaluated the significance of aberrant DNA methyltransferase I (DNMT1) protein expression during gastric carcinogenesis. The protein expression of DNMT1, Muc2, human gastric mucin, E-cadherin, and proliferating cell nuclear antigen was examined immunohistochemically in gastric cancers and corresponding noncancerous mucosae from 134 patients. The DNA methylation status of the CpG islands of the p16, human MutL homologue I (hMLH1), E-cadherin, and thrombospondin-1 (THBS-1) genes and the methylated in tumor (MINT)-1, -2, -12, and -31 clones was examined by methylation-specific polymerase chain reaction and combined bisulfite restriction enzyme analysis. Epstein-Barr virus (EBV) infection was detected by in situ hybridization. Nuclear immunoreactivity for DNMT1 was not detected in any of the noncancerous epithelia, except in proliferative zones (positive internal control), but was found in 97 (72%) of the gastric cancers. DNMT1 overexpression correlated significantly with poorer tumor differentiation (P < 0.001), but not with the phenotype (gastric type versus intestinal type) of the cancer cells. it also correlated significantly with DNA hypermethylation of the CpG islands of the hMLH1 (P = 0.024) and THBS-1 genes (P = 0.043), and with the CpG island methylator phenotype in the gastric cancers (P = 0.007). Reduced E-cadherin expression correlated significantly with poorer tumor differentiation (P = 0.002), DNA hypermethylation of the E-cadherin gene (P < 0.001) and DNMT1 overexpression (P = 0.014). DNMT1 overexpression was also associated with EBV infection (a potential etiological factor in gastric carcinogenesis) but not with the proliferative activity of the cancer cells as indicated by the proliferating cell nuclear antigen-labeling index. These results suggest that DNMT1 overexpression may not be just a secondary effect of increased cancer cell proliferative activity, but may be associated with EBV infection and other etiological factors during gastric carcinogenesis. Furthermore, DNMT1 may play a significant role in the development of poorly differentiated gastric cancers by inducing frequent DNA hypermethylation of multiple CpG islands.