CENP-U调控乳腺癌发生过程的功能研究

Centromere protein (CENP-U) gene, as an important constitutive kinetochore component, plays significant roles in cell caryomitosis. However, the biological functions and potential molecular mechanism of CENP-U in breast cancer tumorigenesis remains largely unclear. Our previous research found that about 25 % of transgenic mice with CENP-U amplified had suffered breast cancer in body surface. Also, in highly aggressive breast cancer cell lines, CENP-U presented the highest expression.Furthermore,the CENP-U protein expression obviously increased in human invasive breast carcinoma compared with the normal gland and intra-ductal tissue. Therefore, based on these results, we hypothesized: CENP-U could be as an oncogene and play an important role in breast cancer tumorigenesis and development. Our research aims to study the role and mechanism of CENP-U in the tumorigenesis and development of breast cancer as well as by using the high-throughput proteomic techniques to determine the key cytokines that regulate this process. Through this we will establish a CENP-U core protein network system and analyze the molecular mechanisms of CENP-U involved in the process of breast cancer occurrence . Eventually, it will provide a new molecular target for the early diagnosis and accurate individualized treatment of breast cancer by constructing a new breast cancer prognosis and treatment efficacy evaluation system using CENP-U as the bio-marker.

CENP-U作为着丝粒复合物的重要组成部分参与细胞的有丝分裂，但其在乳腺癌发生过程中的生物学功能及潜在的分子机制尚不明确。本课题组前期研究发现在CENP-U扩增的转基因小鼠中约25%罹患乳腺癌，同时在细胞系中CENP-U以高侵袭性的三阴性乳腺癌细胞表达最高，而且我们还发现浸润性乳腺癌组织中CENP-U的蛋白表达水平较正常腺体及导管内癌组织均显著增加。基于上述结果，我们提出假设：CENP-U在某种程度上可作为癌基因在乳腺癌发生过程中发挥重要作用。因而，本课题拟探讨CENP-U在乳腺癌发生过程中的生物学功能，并通过利用高通量蛋白质组学技术确定此过程中CENP-U调控的关键细胞因子，确立以CENP-U 为核心的蛋白网络调控体系并解析其参与乳腺癌发生过程的分子机制，最终建立以CENP-U为标志物的乳腺癌治疗疗效评估及预后预测体系，从而为乳腺癌的早期诊断及精准个体化治疗提供新的分子靶标。

着丝粒蛋白U (CENPU)是一种对有丝分裂至关重要的着丝粒成分，与多种癌症的肿瘤发生有关;然而，它在乳腺癌中的作用却鲜为人知。阴性乳腺癌(TNBC)的特点是血管密度高，但抗血管生成治疗效果不佳。本研究旨在探讨其在TNBC中的表达及其促进血管生成的功能。免疫组织化学染色显示CENPU在TNBC组织中高表达，且CENPU高表达患者更容易发生远处转移并且总生存期缩短。敲低TNBC细胞中CENPU抑制血管内皮生长因子A（VEGFA）的产生，并显著减少体外人脐静脉内皮细胞的小管形成和迁移。在小鼠异种移植模型中，敲低CENPU可减少TNBC肿瘤的生长，并减少CD31 +微血管的密度。机制研究表明CENPU是通过抑制环氧合酶2（COX-2）的泛素化和蛋白酶体降解，激活COX-2–p-ERK–HIF-1α–VEGFA信号通路来来促进血管生成的。综上所述，我们的结果证明了CENPU在COX-2介导的血管生成信号中的关键作用，并确定了CENPU在调节TNBC中的血管生成中的作用。