The anticancer effects of 5-aza-2'deoxycytidine as a DNA demethylation agent on NNK-induced rat hepatocellular carcimonas

5-aza-2脱氧胞苷作为DNA去甲基化剂对NNK诱导的大鼠肝细胞癌的抗癌作用

基本信息

批准号：
15590667
负责人：
SASAKI Shigeru
金额：
$ 2.24万
依托单位：
Sapporo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590667/
关键词：
methylation NNK DNA array hepatocellular carcinoma DNA demethylation agent NNKラット

项目摘要

Hepatocellular tumors were induced in male Fischer 344 rats by treatment with the 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) three times a week (50 mg/kg intraperitoneally injection) for 20 weeks. Based on histopathological analysis, these tumors were diagnosed as carcinomas (12 nodules/total 28 nodules) and adenomas (16 nodules/total 28 nodules).RNA and DNA were isolated from these hepatocellular carcinomas. To determine gene expression changes associated with NNK exposure to genotoxic carcinogens, these RNA were subjected to microarray analysis. A number of genes were down-regulated by NNK exposure compared with controls. The methylation status of these down-regulated genes were determined by methylation-specific PCR (MSP). Overall, the promoter region hypermethylation of the p16 and E-cadherin genes were detected. The protein expression levels of p16 and E-cadherin were examined by immunohistochemical staining. The expression levels of these proteins were also down-regulated.The anticancer effects of 5-aza-2'deoxycytidine once a week (1 mg/kg intraperitoneally injection) as a DNA demethylation agent on NNK-induced rat hepatocellular carcimonas were investigated. Our results suggested that 5-aza-2'deoxycytidine did not influence on the potency of hepatocarcinogenesis induced by NNK, the progression of hepatocellular carcinomas and the methylation status of p16 and E-cadherin genes methylated with NNK treatment.

通过用4-甲基硝基氨基-1-（3-吡啶基）-1-丁酮（NNK）治疗雄性Fischer 344大鼠，在雄性Fischer 344大鼠中诱导肝细胞质肿瘤，每周3次（50 mg/kg腹膜内伤害）20周。基于组织病理学分析，这些肿瘤被诊断为癌（12个结节/总计28个结节）和腺瘤（16个结节/总计28个结节）。从这些肝细胞癌中分离出RNA和DNA。为了确定与NNK暴露于遗传毒性致癌物相关的基因表达变化，对这些RNA进行了微阵列分析。与对照组相比，NNK暴露的许多基因被下调。这些下调基因的甲基化状态通过甲基化特异性PCR（MSP）确定。总体而言，检测到p16和e-钙粘蛋白基因的启动子区域高甲基化。通过免疫组织化学染色检查了p16和e-钙粘蛋白的蛋白表达水平。这些蛋白质的表达水平也被下调。研究每周一次（腹膜内注射1 mg/kg）对NNK诱导的大鼠肝细胞癌的DNA脱甲基化剂的抗癌作用。我们的结果表明，5-AZA-2'DEOXYCYTIDINE不影响NNK诱导的肝癌发生的效力，肝细胞癌的进展以及P16和E-钙粘蛋白基因甲基化的甲基化状态和NNK治疗的甲基化状态。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Integration of interferon-α/β signaling to p53 responses in tumour suppression and antiviral defence.

干扰素-α/β 信号转导与 p53 反应在肿瘤抑制和抗病毒防御中的整合。

DOI：
发表时间：
2003
期刊：
Nature 424
影响因子：
0
作者：
Hinoda Y;Sasaki S;Ishida T;Imai K.;Tsunada S;Takaoka A. et al.
通讯作者：
Takaoka A. et al.

Integration of interferon-α/β signaling to p53 responses in tumour suppression and antiviral defence

干扰素-α/β 信号转导与 p53 反应在肿瘤抑制和抗病毒防御中的整合

DOI：
发表时间：
2003
期刊：
Nature 424(6948)
影响因子：
0
作者：
Takaoka A;Hayakawa S;Yanai H;Stoiber D;Negishi H;Kikuchi H;Sasaki S;Imai K;Shibue T;Honda K;Taniguchi T.
通讯作者：
Taniguchi T.

Monoclonal antibodies as effective therapeutic agents for solid tumors

DOI：
10.1111/j.1349-7006.2004.tb03319.x
发表时间：
2004-08-01
期刊：
CANCER SCIENCE
影响因子：
5.7
作者：
Hinoda, Y;Sasaki, S;Imai, K
通讯作者：
Imai, K

Differential roles of alterations of p53, p16, and SMAD4 expression in the progression of intraductal papillary-mucinous tumors of the pancreas

p53、p16 和 SMAD4 表达变化在胰腺导管内乳头状粘液性肿瘤进展中的不同作用

DOI：
发表时间：
2003
期刊：
Oncol Rep. 10(1)
影响因子：
0
作者：
Sasaki S;Yamamoto H;Kaneto H;Ozeki I;Adachi Y;Takagi H;Matsumoto T;Itoh H;Nagakawa T;Miyakawa H;Muraoka S;Fujinaga A;Suga T;Satoh M;Itoh F;Endo T;Imai K.
通讯作者：
Imai K.

Differential roles of alterations of p53, p16, and SMAD4 expression in the progression of intraductal papillary-mucinous tumors of the pancreas.

p53、p16 和 SMAD4 表达的改变在胰腺导管内乳头状粘液性肿瘤进展中的不同作用。