细胞外铜离子介导CD147自聚合促肝癌细胞恶性表型的结构与功能关系研究

项目名称： 细胞外铜离子介导CD147自聚合促肝癌细胞恶性表型的结构与功能关系研究

项目编号： No.31270015

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 宋斐

作者单位： 中国人民解放军第四军医大学

项目金额： 80万元

中文摘要： CD147是高表达于多种癌细胞上的肿瘤标志分子，具有促进癌细胞增殖和转移等功能。申请人前期研究了CD147作为受体与CyPA相互作用以及与其剪切异构体聚合的结构与功能关系，相关文章在JBC等杂志发表。研究中我们发现细胞外铜离子能够介导CD147聚合，并通过膜上CD147促进肝癌细胞分泌基质金属蛋白酶。许多报道显示癌组织中铜离子浓度大幅提高，而铜离子螯合剂能抑制肿瘤增殖和血管生成，但相关机制仍不清楚。本研究计划利用NMR和X射线晶体学等手段深入研究铜离子介导CD147聚合的结构基础，同时利用独有的敲除CD147肝癌细胞模型，结合细胞分子生物学方法，揭示铜离子介导CD147聚合调控肝癌细胞侵袭转移等恶性表型的结构与功能关系及功能靶位，阐明铜离子介导CD147聚合促肝癌细胞恶性表型分子机制。本研究将加深对CD147作用机制的认识，发现铜离子与癌细胞侵袭转移的关系，并为临床治疗提供新思路和新靶位。

中文关键词： 肝癌；受体；细胞外二价铜离子；CD147/Basigin；基质金属蛋白酶

英文摘要： CD147 is a wildely distributed protein and is highly enriched on the surface of malignant tumor cells, which promotes tumor invasion and metastasis. We have identified its ligands CyPA and CD147 isoform binding site on CD147, and clarified the structure-function relationship of the interaction between CD147 and its ligands. Based on these results, we have published several paper on JBC and MCB journals. During the study of CD147 self-association, we found extracellular copper ion can mediate CD147 self-association, and copper ion promoted MMP secretion of hepatoma cell via We have identified CyPA and CD147 isoform binding site on CD147, and clarified the structure-function relationship of the interaction between CD147 and its ligands, which results have been published on JBC and MCB journals. During the study on CD147 self-association mechanism, we found extracellular copper ion can mediate CD147 self-association, and copper ion promoted MMP secretion of hepatoma cell via CD147. In addition, it has been reported that copper level measured by X-ray fluorescence in tumor is higher than normal tissue, and specific copper chelate can inhibit tumor proliferation and angiogenesis, but the mechanism still remains unclear. Based on our previous studies, we will determine the structure of copper mediated CD147 self-assoc

英文关键词： hepatocellular carcinoma；receptor；extracellular divalent copper；CD147/Basigin；matrix metalloproteinase