PRC1和PRC2共同调控Snail介导的上皮-间质转换在胰腺肿瘤转移机制中的研究

项目名称： PRC1和PRC2共同调控Snail介导的上皮-间质转换在胰腺肿瘤转移机制中的研究

项目编号： No.81472237

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： 彭承宏

作者单位： 上海交通大学

项目金额： 72万元

中文摘要： 上皮-间质转换（EMT）在肿瘤转移中发挥重要作用。Snail作为诱导EMT的重要因子，是连接多种促肿瘤转移信号通路的中心分子，其诱导EMT的机制尚不清楚。我们前期研究发现多梳蛋白成员Ring1B与Snail在胰腺癌中表达升高，两者正相关且联合预示胰腺癌预后。在胰腺癌细胞中,内源Snail与Ring1A/B特异结合，同时沉默Ring1A/B可以削弱Snail对靶基因的转录抑制作用。由此推测: Snail招募Ring1A/B至靶基因启动子区，通过PRC1介导组蛋白H2A泛素化，协同PRC2介导H3K27甲基化，调控基因表达并诱导EMT。本课题拟深入探讨Snail/PRC1/PRC2复合物在基因调控网络中的相互作用，以及在EMT过程中的表观调控机制，最后通过动物实验验证；结合Snail/PRC1/PRC2与临床预后的相关性，综合评估PRC1/PRC2作为抗肿瘤靶点的潜在可能性，实现研究结果转化。

中文关键词： C11_胰肿瘤；组蛋白修饰；Polycomb；Snail；上皮-间质转换

英文摘要： Pancreatic cancer is characterized by extremely aggressive due to early metastasis, in the process of which Epithelial-mesenchymal transition (EMT) plays a crucial role. Transcriptional factor Snail is a key regulator of EMT, as well as a convergence point at the downstream of many tumor-promoting pathways. However, the molecular mechanism governing Snail to induce EMT and metastasis is unclear. Our preliminary studies demonstrated that Snail and the polycomb protein Ring1B was upregulated in pancreatic cancer, and their expression patterns were positively correlated. Combination of high Snail and high Ring1B were associated with clinical prognosis. Endogenous Ring1A/B interact with Snail and simultaneous depletion of Ring1A and Ring1B in pancreatic cancer cells compromises Snail-mediated transcriptional repression. We hypothesis that PRC1 recruited to the target promoter region by Snail can catalyze ubiquitination of H2A，and cooperate with PRC2 which are responsible for H3K27 methylation, leading to transcriptional repression of target genes. Thus，the aims of this application are to investigate the role of Snail/PRC1/PRC2 complexes in the crosstalk network during regulating gene repression and EMT, verify the epigenetic regulation mechanisms by in vivo animal experiments，evaluate the potentials of PRC1/PRC2 as novel antitumor targets，and accomplish translational research from bench to bedside.

英文关键词： pancreatic cancer;histone modification;Polycomb;Snail;Epithelial-mesenchymal Transition