Alterations of DNA methyltransferases during multistage human carcinogenesis

DNMT1在慢性肝炎或肝硬化肝组织中的表达水平高于正常肝组织，在肝细胞癌（hcc）中的表达水平更高。DNMT1在hcc中的过表达与较差的肿瘤分化和门静脉受累相关。DNMT1在具有炎症背景和胰腺上皮内瘤变的胰腺外周导管上皮中过表达。DNMT1过表达与胰腺癌的侵袭性和甲基化肿瘤相关基因的积累有关。肝癌和胰腺癌患者DNMT1过表达预后较差。DNMT1在胃癌中的过表达与CpG岛甲基化表型和eb病毒感染相关。在与人乳头瘤病毒感染密切相关的宫颈上皮内瘤变中也发现DNMT1过表达。在非癌性尿路上皮中，没有明显的组织学发现，更多地暴露于尿液中的致癌物中，DNMT1过表达先于细胞增殖活性的增加。DNMT1过表达可能通过诱导区域DNA高甲基化参与从癌前状态到恶性进展的多阶段癌变。在显示慢性肝炎或肝硬化和hcc的肝组织中检测到中心体周围卫星区DNA低甲基化。DNMT3b对于这些区域的DNA甲基化是特别需要的。正常肝组织仅显示微量的DNMT3b4，这是一种不显示DNMT活性的剪接变体。DNMT3b4在慢性肝炎或肝硬化及hcc肝组织中的表达水平与中心点周围卫星区DNA低甲基化程度相关。DNMT3b4 mRNA与DNMT3b3 mRNA的比值（DNMT3b3是正常肝组织中的主要活性变异）也与DNA低甲基化程度相关。DNMT3b4可能与DNMT3b3竞争瞄准中心周围卫星区域。在DNMT3b4转染体中观察到卫星2上的DNA去甲基化。肝癌发生过程中，DNMT3b4过表达可能通过中心体周围卫星区DNA低甲基化导致染色体不稳定。少

The expression level of DNMT1 was higher in liver tissues showing chronic hepatitis or cirrhosis than in normal liver tissues, and was even higher in hepatoceellular carcinomas (HCCs). DNMT1 overexpression in HCCs is correlated with poorer tumor differentiation and portal vein involvement. DNMT1 overexpression was detected in peripheral pancreatic ductal epithelia with an inflammatory background and pancreatic intraepithelial neoplasias. DNMT1 overexpression is associated with aggressiveness of pancreatic cancers and accumulation of methylated tumor-related genes. Patients with HCCs and pancreatic cancers showing DNMT1 overexpression have a poorer prognosis. DNMT1 overexpression in stomach cancers is correlated with CpG island methylator phenotype and Epstein-Barr virus infection. DNMT1 overexpression was also found in cervical intraepithelial neoplasias closely associated with human papillomavirus infection. In non-cancerous urothelia showing no remarkable histological findings which … More can be exposed to carcinogens in the urine, DNMT1 overexpression preceded increased cell proliferative activity. DNMT1 overexpression may participate in multistage carcinogenesis, from precancerous conditions to malignant progression, through induction of regional DNA hypermethylation.DNA hypomethylation of pericentromeric satellite regions was detected in liver tissues showing chronic hepatitis or cirrhosis and HCCs. DNMT3b is specifically required for DNA methylation of such regions. Normal liver tissues show only a trace level of DNMT3b4, a splice variant not showing DNMT activity. The expression level of DNMT3b4 in liver tissues showing chronic hepatitis or cirrhosis and HCCs was correlated with the degree of DNA hypomethylation of pericentromeric satellite regions. The ratio of DNMT3b4 mRNA to DNMT3b3, the major active variant in normal liver tissues, was also correlated with the degree of DNA hypomethylation. DNMT3b4 may compete with DNMT3b3 for targeting to pericentromeric satellite regions. DNA demethylation on satellite 2 was observed in DNMT3b4 transfectants. DNMT3b4 overexpression may lead to chromosomal instability through DNA hypomethylation of pericentromeric satellite regions during hepatocarcinogenesis. Less