干扰蛋白酶活化受体2 （PAR2）信号诱导肿瘤干细胞凋亡的分子机制研究

项目名称： 干扰蛋白酶活化受体2 （PAR2）信号诱导肿瘤干细胞凋亡的分子机制研究

项目编号： No.81472560

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： 汪红英

作者单位： 中国医学科学院肿瘤医院

项目金额： 64万元

中文摘要： 肿瘤干细胞具有重建肿瘤的能力和特性，在肿瘤的发生、复发和转移过程中至关重要。最近研究发现：微环境与肿瘤干细胞的维持和功能密不可分。肿瘤微环境中富集大量的蛋白酶，而其中某些蛋白酶可以选择性地激活蛋白酶活化受体2（PAR2）参与肿瘤的发生发展。癌组织周边是蛋白酶富集的地方，恰巧也是肿瘤干细胞富集的区域，那么蛋白酶是否与肿瘤干细胞有关呢？我们前期研究发现，作为蛋白酶的感受器，PAR2在结肠癌组织中高表达并与转移显著正相关，敲降PAR2显著抑制肿瘤细胞的体内致瘤性。尤为重要的是，干扰PAR2信号通路选择性地诱导CD133+细胞的凋亡(而CD133是已知的肿瘤干细胞标志物之一)。因此，在本项研究中我们将明确蛋白酶-PAR2信号通路与肿瘤干细胞的关系，探讨PAR2信号通路特异性调节肿瘤干细胞调亡的分子机制，及其作为肿瘤治疗干预靶点的可能性。

中文关键词： C08_结；直肠肿瘤；蛋白酶活化受体2；肿瘤干细胞；凋亡；CD133

英文摘要： Cancer stem cell has the ablility to initiate tumor growth and play critical roles in the formation, relaps and metastasis of cancer. Microenvironment emerge to be a key player in the maintenance and regulation of cancer stem cell. Proteinases in the tumor microenvironment promote the carcinogenesis through the selective activation of proteinase activated receptor 2 (PAR2) expressed by cancer cells. The surrounding area of tumor not only fills with proteinases but also is the attractive place for cancer stem cell. So the question is what is the relationship between proteinases and cancer stem cell. Our previous study showed that overexpression of PAR2 was observed in colorectal cancer and positively correlated with metastasis. Moreover, knockdown of PAR2 significantly reduced tumoriginecity of cancer cell in vivo. Most importantly, deficiency of PAR2 signaling selectively induced apoptosis in CD133+ population, which is a well-known marker of cancer stem cell. Therefore, the aims of current study are 1）to confirm the correlationship between proteinase-PAR2 signaling and cancer stem cell, 2）to study the mechanisms by which deficiency of PAR2 signaling enhance the apoptosis in CD133+ cancer stem cell and also 3）to study whether PAR2 is a potential anti-cancer target for colorectal carcinoma.

英文关键词： Colorectal carcinoma;Proteinase Activated Receptor 2;Cancer stem cell;apoptosis;CD133