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

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.

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。

p21活化激酶4与乳腺癌的侵袭转移密切相关。但是，p21活化激酶4介导的上皮间质转化的乳腺癌细胞侵袭转移的机制尚未明确。因此，探讨新的p21活化激酶4的底物与相互作用蛋白，从而提示上皮间质转化介导的乳腺癌细胞的侵袭与转移是非常具有临床意义的。我们选取了MCF-7与MDA-MB-231两种乳腺癌细胞作为研究对象，结果发现，p21活化激酶4能通过磷酸化色氨酸675位点稳定β-连环蛋白，并介导β-连环蛋白发生核转位。该磷酸化途径能使胞膜上β-连环蛋白-E-cadherin复合物水平下降，减少细胞之间的粘附作用，进一步增加细胞的上皮间质转化；同时，该磷酸化途径诱导β-catenin/TCF4/LEF-1复合物形成，进一步促进胞核中下游蛋白基质金属蛋白酶9的表达，导致乳腺癌细胞发生上皮间质转化。我们的研究分别从组织/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。