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肝细胞癌变中IGF-II基因启动子结构、功能和突变的研究

批准号30070853 学科分类环境地球化学 ( D0707 )
项目负责人麦碧娴 负责人职称 依托单位暨南大学
资助金额0.00
万元
项目类别重点项目 研究期限2001 年 01 月 01 日 至
2003 年 12 月 01 日
中文主题词肝细胞癌; 胰岛素样生长因子Ⅱ; 基因;启动子
英文主题词Hepatocellular carcinoma;Insulin-like growth factor Ⅱ;Genes;Promoters

摘要

中文摘要 通过观察肝癌、癌旁肝和慢性肝病中IGF-II基因结构调控区域的改变或突变规律,以及肝赴蠬BV-DNA整合对IGF-II基因不同启动子活性的影响,探讨肝细胞癌变过程中IGF-II基因启动子异常激活的始动原因以及与HBV-DNA整合状态的因果关系,进一步阐明IGF-II在肝细┍浠浦械淖饔茫哂兄傅几伟┑姆乐渭傲俅苍缙谡镏蔚囊庖濉O
英文摘要 Human insulin-like growth factorⅡ(IGF-Ⅱ)gene contains nine exons and four different ?promoters(P1-P4).In fetal and neonatal livers promoters P2,P3 and P4 are active(the activity of P3 is the highest) and promoter P1 is inactive. In adult liver,however,P1 becomes dominant and the activities of P2-P4 decrease significantly or are lost. In recent years it has been found that the overexpression of IGF-Ⅱgene was observed in hepatocarcinogenesis, which is correlated with the reactivation of P3 and P4 and the loss of P1 activity. But the mechanisms responsible for the control of P1,P3 and P4 are not well understood. Thus in the present study we have cloned P1-P4 of IGF-Ⅱgene, and DNA sequences and methylation status of four promoters have been detected in the livers of patients with chronic hepatitis, cirrhosis and hepatocellular carcinoma(HCC).Structure of four promoters and their interaction with transcription factors have been analyzed in cell lines using dual luciferase reporter assay system and electromobility shift assay(EMSA)in order to determine the mechanisms by which P1,P3 and P4 are controlled in hepatocellular carcinogenesis.The data have indicated that:①there were no deletion and mutation in the four promoters of IGF-Ⅱgene in all tissue samples, which may not be related to the mechanisms involved in the regulation of IGF-Ⅱoverexpression; ②the methylation of P1 and no methylation of P3 and P4 were found in most of the tumor tissues and nontumorous tissues neighboring carcinoma from HCC patients and these abnormal changes may be associated with the control mechanisms of the reactivation of P3 and P4 and the loss of P1 activity; ③the weak activity or no activity of P1 and the high activity of P3 and P4 may be involved in the expression level changes of corresponsive transcription factor(s) and /or expression of additional factors in human hepatoma cells.
结题摘要 人胰岛素样生长因子Ⅱ(IGF-Ⅱ)基因含9个外显子(E1-E9)和4个不同的启动子(P1-P4)。在胎肝和新生儿肝,启动子P2-P4活化(P3活性最大),P1失活;在成人肝脏,启动子P1活性最大,而P2-P4活性微弱或呈关闭状态。近年发现人IGF-II在肝细胞癌变中常呈过表达状态,且异常表达与P3、P4再活化及P1失活关系密切,但其详细机制尚未明确。为此,本研究首先克隆该基因的P1-P4启动子,并以此为基础观察肝癌、癌旁肝、肝硬化、慢性肝炎组织IGF-Ⅱ启动子有无突变及甲基化水平改变,检测各启动子的转录调控活性,分析其转录调节元件及其与转录因子的相互作用,以探讨肝细胞癌变过程中P3、P4再活化及P1失活的调控机制。结果显示:①本组病例各慢性肝病组织IGF-Ⅱ基因启动子未见突变、缺失等改变,可能与IGF-Ⅱ异常表达的转录调控机制无明显关系;②肝癌、癌旁肝组织P1多出现甲基化,而P3、P4则多数无甲基化,这种改变可能与P3、P4再活化和P1失活的转录调控机制相关;③肝癌细胞中P1活性低下或缺失、P3和P4的高转录活性可能与相应转录因子的水平变化(下调或上调)或表达新的转录因子密切相关。

成果

序号 标题 类型 作者
1 人胰岛素样生长因子Ⅱ基因P1、P3启动子克隆及意义 著作 汤绍辉|杨冬华|舒建昌|黄卫|

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