CD74调控乳腺癌细胞迁移的分子机制

项目名称： CD74调控乳腺癌细胞迁移的分子机制

项目编号： No.81472686

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 苏玲

作者单位： 山东大学

项目金额： 80万元

中文摘要： CD74具有多种生物学功能，在多种肿瘤细胞中高表达，并与高转移乳腺癌相关，但其在乳腺癌细胞中表达及调控转移的机制并不清楚。前期实验表明，CD74可能受p-YB-1调控；抑制CD74表达会降低乳腺癌细胞的迁移能力和F-actin 聚合，同时 Rac1-GTP和p-Cofilin水平下降。基于此，提出如下假说：在乳腺癌细胞中， p-YB-1可能在转录或转录后水平调控CD74表达；CD74与CD44形成复合物，通过TIAM1作为GEF活化Rac1，而PAK1作为其下游效应物，进而通过磷酸化LIMK及Cofilin促进F-actin的重构，最终影响乳腺癌细胞的迁移、侵袭和转移能力。本研究拟利用细胞和动物模型，深入探讨CD74在乳腺癌细胞中表达调控的分子机制，以及通过调控微丝组装重构，最终影响肿瘤细胞迁移、侵袭和转移的分子机制。本研究将加深对乳腺癌转移调控网络的了解，以利于将来抗转移药物的研发。

中文关键词： C21_乳腺肿瘤；CD74；细胞迁移；F-actin；肿瘤转移

英文摘要： CD74 is a multifaceted protein which overexpresses in multiple cancers including breast cancer. Its expression is associated with the breast cancer metastasis. However, the molecular mechanism underlying its expression and functions remains unclear. According to our preliminary study, we found YB-1 knockdown using RNAi technique decreased the expression level of CD74, suggesting CD74 may be regulated by phospho-YB-1 at either the transcriptional or the post-transcriptional level. Moreover, CD74 knockdown could reduce the levels of Rac1-GTP and phosho-Cofilin which both play critical role in F-actin polymerization and eventually the motility of the breast cancer cells. Based on the preliminary data, we raise a hypothesis: CD74 is regulated by phosphor-YB-1, and CD74 forms a complex together with CD44 to interact TIAM1. As a GEF, TIAM1 promotes Rac1 signaling axis including PAK1, LIMK1/2 and Cofilin, leading to F-actin remodeling. Eventually, the ability of cell migration, invasion and metastasis is affected by this signaling axis. Accordingly, the present project is going to use cell and animal models to elucidate the molecular mechanism underlying the modulation of CD74 expression as well as the functions of CD74 in enhancing F-actin remodeling and migration in breast cancer cells. Hopefully, the study of CD74 can help us understand the metastatic signaling network in breast cancer cells. In addition, it will be helpful for developing the novel anti-metastasis drugs for cancer therapy in the future.

英文关键词： breast cancer;CD74;Cell migration;F-actin;Cancer metastasis