抑癌基因ZHX2调控肝癌细胞中DNMT3B表达的分子机制研究

项目名称： 抑癌基因ZHX2调控肝癌细胞中DNMT3B表达的分子机制研究

项目编号： No.31301077

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 何影

作者单位： 山东大学

项目金额： 23万元

中文摘要： ZHX2是一个具有锌指结构和同源框的转录抑制因子，具有抑癌基因活性。过表达ZHX2的肝癌细胞基因芯片和ChIP-on-chip结果提示：ZHX2能够调控表观修饰基因DNMT3B的转录表达。DNMT3B在多种恶性肿瘤，包括肝细胞肝癌（HCC）中异常高表达。目前已开发出针对DNA甲基转移酶（DNMT）的化疗药物用于血液肿瘤疾病的临床治疗，但这些化学药物对于包括HCC在内的实体瘤的治疗效果有限。本课题在前期结果的基础上，首先通过瞬时转染技术在肝癌细胞模型中进一步明确ZHX2对DNMT3B的表达调控作用。进而研究ZHX2抑制DNMT3B表达后是否影响肿瘤抑制基因启动子区域的甲基化水平。最后从寻找顺式作用元件和探讨ZHX2的反式作用功能域两个角度深入探讨肝癌细胞中ZHX2调控DNMT3B表达的分子机制，为开发针对DNMT的生物制剂用于HCC的临床治疗提供理论依据。

中文关键词： DNA甲基转移酶；抑癌基因；ZHX2；基因调控；肝细胞肝癌

英文摘要： Zinc-fingers and homeoboxes 2 (ZHX2) protein is a transcriptional repressor and functions as a tumor suppressor gene (TSG). The gene chip and ChIP-on-chip analysis showed that ZHX2 may regulate the transcriptional expression of DNA methyltransferase 3B (DNMT3B), an epigenetic gene. DNMT3B was abnormally high expressed in different types of human cancers, including hepatocelluar carcinoma (HCC). The chemical agents, azacitidine and decitabine, targeting DNA methyltransferase (DNMT) have been used for clinical treatment for haematological malignancies. However, early clinical trials showed that these DNMT inhibitors have low anticancer activity and significant toxicity in different solid tumors, including HCC. In this study, we will try to explore the mechanism of ZHX2 regulating DNMT3B expression, including the cis-acting element in the DNMT3B promoter and trans-acting functional domains of ZHX2.And we will also study the effect on the methylation level of TSGs' promoter. Our study should be helpful to develop biological inhibitors of DNMT for HCC therapy.

英文关键词： DNA methyltransferase；tumor suppressor gene；ZHX2；gene regulation；Hepatocellular Carcinoma