角蛋白18在BCPR介导的乳腺癌细胞多药耐药中的作用和机制研究

项目名称： 角蛋白18在BCPR介导的乳腺癌细胞多药耐药中的作用和机制研究

项目编号： No.81502641

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 师锐赞

作者单位： 山西医科大学

项目金额： 18万元

中文摘要： 乳腺癌耐药蛋白(BCRP)是肿瘤干细胞(CSCs)标志物之一，介导多种肿瘤的多药耐药(MDR)，但其调控机制不清。上皮间质转化(EMT)是肿瘤侵袭转移的重要机制，NF-κB/snail是其调节通路之一。最新研究发现，EMT与CSCs、BCRP介导的MDR均相关。我课题组前期结果提示，角蛋白(CK18)与BCRP介导的乳腺癌MDR有关，且抑制CK18可上调snail诱导EMT。据此，我们推测“CK18可能经NF-κB/snail通路诱导EMT调控BCRP介导的乳腺癌MDR”。本课题先观察CK18表达、EMT相关蛋白及NF-κB/snail通路、CSCs比例在人乳腺癌敏感株和BCRP高表达耐药株的差异，并进一步抑制CK18或阻断NF-κB/snail通路诱导EMT，观察对BCRP、CSCs的影响，阐明CK18调控BCRP介导的乳腺癌MDR的机制。本课题的完成将为恶性乳腺癌的有效防治提供新思路。

中文关键词： 角蛋白18；乳腺癌耐药蛋白；多药耐药；上皮间质转化；NF-κB/snail通路

英文摘要： Breast cancer resistant protein (BCRP) acts as one of markers of cancer stem cells (CSCs) and mediates the multidrug resistance (MDR) in a number of malignancies, but the mechanism of regualation on it is not clear. Epithelial-mesenchymal transition (EMT) is one of the important mechanisms of tumor invasion and metastasis, and NF-κB/snail pathway plays an important role in the regulation of EMT. The newest studies have demonstrated that EMT correlates with BCRP -mediated MDR and promotes the production of CSCs. Our laboratory previous studies found that cytokeratin 18 (CK18) was involved in MDR in breast cancer, inhibition of CK18 affected the expression of snail and induced EMT. Therefore, we speculate that CK18 induces EMT and regulates BCRP-mediated MDR in breast cancer through NF-κB/snail pathway. To test this hypothesis, the differential expression of CK18, EMT- associated proteins and pathway and CSCs markers were detected in human breast cancer cells, including drug-sensitive and -resistant cells with the MDR phenotype known as overexpression of BCRP. To explore the mechanism involved of CK18 in BCRP-mediated MDR, induction EMT via inhibition of CK18 or blockade of NF-κB/snail is to be executed to observe the effect on the BCRP expression and function, the ratio of CSCs. This study will provide new insights into prevention and treatment of malignant breast cancer.

英文关键词： cytokeratin 18 (ck18);breast cancer resistant protein (BCRP);multidrug resistance (MDR);Epithelial-mesenchymal transition (EMT);NF-κB/snail pathway