PAK4介导β-catenin的亚细胞转位调控乳腺癌上皮间质转化的机制研究

项目名称： PAK4介导β-catenin的亚细胞转位调控乳腺癌上皮间质转化的机制研究

项目编号： No.81502308

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 欧阳雯

作者单位： 武汉大学

项目金额： 18万元

中文摘要： 上皮间质转化（EMT）与肿瘤细胞的侵袭转移密切相关。EMT的一个重要分子是β-catenin,决定β-catenin是发挥黏附还是转录功能的关键因素是其在细胞内的定位。我们前期研究发现：p21活化激酶PAK4与β-catenin相互作用，两者在乳腺癌细胞中共定位；且β-catenin能上调EMT的诱发因素MMP-9启动子的转录活性。因此，本项目以乳腺癌为研究对象，首先检测PAK4/β-catenin的表达对乳腺癌侵袭转移和肿瘤细胞EMT的影响；其次探讨PAK4通过何种机制介导β-catenin在细胞内发生转位；然后研究β-catenin入核后，如何诱导MMP-9的转录，促进乳腺癌细胞发生EMT。本研究分别从组织/细胞/分子水平阐释PAK4所介导的β-catenin的胞内转位在调控MMP-9表达和EMT中的关键作用，为探索乳腺癌的生物学治疗新靶点奠定理论基础。

中文关键词： 乳腺肿瘤；p21活化激酶4；β-连环蛋白；亚细胞转位；上皮间质转化

英文摘要： Epithelial-mesenchymal transition(EMT) is closely related to the invasion and metastasis of tumor.β-catenin is a significant molecule in the progress of EMT.The subcellular translocation of β-catenin plays a crucial role in switching between adhesion and transcription function.In our previous study,we found that β-catenin colocalized and interacted with p21-activated kinase PAK4,and β-catenin binding with TCF / LEF transcription factor could upregulate the transcription of MMP-9, which was considered as the inducing factor of EMT.Consequently,we will take breast cancer as the target to research in this study.Firstly,the correlation between expression level of PAK4/β-catenin and neoplasm invasiveness,neoplasm metastasis,EMT will be analyzed in breast cancer tissues and cell lines.Secondly,the mechanisms of PAK4 mediated subcellular translocation of β-catenin will be explored.Thirdly,the transcription complex of β-catenin/TCF/LEF initiating the transcription of MMP-9 will be examined.Eventually,the relationship between expression of PAK4/β-catenin and EMT,and the ability of invasion and metastasis of breast cells will be evidenced.Our study will explain PAK4 mediated subcellular translocation of β-catenin plays an important role in the transcription of MMP-9 and the progress of EMT on the level of tissue/cell/molecule,and it may provide significantly theoretical basis for finding a novel target of the biological therapy in breast cancer.

英文关键词： breast tumor;p21-activated kinase 4;β-catenin;subcellular translocation;epithelial mesenchymal transition