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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

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）中表达水平更高。 HCC 中 DNMT1 过度表达与肿瘤分化较差和门静脉受累相关。在具有炎症背景的外周胰腺导管上皮和胰腺上皮内瘤变中检测到 DNMT1 过度表达。 DNMT1 过度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。 DNMT1 过度表达的 HCC 和胰腺癌患者预后较差。胃癌中 DNMT1 过度表达与 CpG 岛甲基化表型和 Epstein-Barr 病毒感染相关。在与人乳头瘤病毒感染密切相关的宫颈上皮内瘤变中也发现了DNMT1过度表达。在非癌性尿路上皮中，没有明显的组织学发现（可以暴露于尿液中的致癌物质），DNMT1 过度表达先于细胞增殖活性增加。 DNMT1 过表达可能通过诱导区域 DNA 高甲基化参与多阶段癌发生，从癌前病变到恶性进展。在显示慢性肝炎或肝硬化和 HCC 的肝组织中检测到着丝粒周围卫星区域的 DNA 低甲基化。 DNMT3b 对于这些区域的 DNA 甲基化是特别需要的。正常肝组织仅显示痕量水平的 DNMT3b4，这是一种不显示 DNMT 活性的剪接变体。慢性肝炎或肝硬化和肝癌的肝组织中DNMT3b4的表达水平与着丝粒周围卫星区DNA低甲基化程度相关。 DNMT3b4 mRNA 与 DNMT3b3（正常肝组织中主要的活性变体）的比率也与 DNA 低甲基化程度相关。 DNMT3b4 可能与 DNMT3b3 竞争靶向着丝粒周围卫星区域。在 DNMT3b4 转染子中观察到卫星 2 上的 DNA 去甲基化。 DNMT3b4 过表达可能在肝癌发生过程中通过着丝粒周围卫星区域的 DNA 低甲基化导致染色体不稳定。较少的