Alterations of DNA methyltransferases during multistage human carcinogenesis

人类多阶段致癌过程中 DNA 甲基转移酶的变化

基本信息

批准号：
15390120
负责人：
KANAI Yae
金额：
$ 9.79万
依托单位：
National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2006
项目状态：
已结题

项目摘要

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

在表现出慢性肝炎或肝硬化的肝组织中，DNMT1的表达水平高于正常肝组织，并且在肝细胞癌（HCCS）中甚至更高。 HCC中的DNMT1过表达与较差的肿瘤分化和门静脉的参与相关。在外周胰腺外周上检测到DNMT1过表达，具有炎症背景和胰腺上皮内肿瘤。 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。 HCCS和胰腺癌的患者表现出DNMT1过表达的预后较差。 Stallch癌中的DNMT1过表达与CpG岛甲基表型和Epstein-Barr病毒感染相关。在与人乳头瘤病毒感染密切相关的上皮内肿瘤中也发现了DNMT1过表达。在非癌性尿路上皮中，没有明显的组织学发现，这些发现可能会暴露于尿液中的致癌物，DNMT1过表达之前是细胞增殖活性增加。 DNMT1过表达可以通过诱导区域DNA高甲基化来参与多阶段的癌变，从癌前条件到恶性进展。在表现出慢性肝炎或cirrhosis和HCCS的肝脏组织中检测到了美肠粒卫星卫星区域的DNA低甲基化。 DNMT3B是特异性的，用于此类区域的DNA甲基化。正常的肝脏尖端仅显示DNMT3B4的痕量水平，剪接变体未显示DNMT活性。 DNMT3B4在肝尖端显示出慢性肝炎或肝硬化和HCC的表达水平与周围粒细胞卫星区域的DNA甲基化程度相关。 DNMT3B4 mRNA与DNMT3B3（正常肝尖端中的主要活性变体）的比率也与DNA降压甲基化程度相关。 DNMT3B4可以与DNMT3B3竞争，以靶向围层卫星区域。在DNMT3B4转化体中观察到卫星2上的DNA去甲基化。 DNMT3B4的过表达可能会通过肝癌发生期间的牙粒卫星区域的DNA低甲基化导致染色体不稳定性。较少的