EZH2调控FBW7在三阴乳腺癌紫杉醇耐药机制及其应用的研究

Drug resistance is the bottleneck of overcome for the successful treatment of cancer; most TNBC patients with advanced disease eventually develop chemotherapy drug-resistance. However, the mechanisms are not completely understood. FBW7 is a well-characterized tumor suppressor that targets numerous oncoproteins for destruction, including MCL1 which associated with paclitaxel drug resistance. Genomic mutation or deletion of FBW7 has been usually shown in series types of human cancers; however, it is still unclear about the upstream signaling pathway regulating FBW7 expression. EZH2 is the catalytic core protein which catalyses the methylation of histone and mediates the silencing of target genes that are involved in fundamental cellular processes, such as cancer. Ours preliminary work demonstrated that overexpression of EZH2 were associated with lymph node metastasis, distant metastatic relapse, and poor prognosis in TNBC patients. Therefore, we hypothesis that overexpression of EZH2 could silencing of FBW7 by catalyzing the methylation of its histone, and subsequently increases MCL1 abundance, resulting in cancer cell developed drug resistance in TNBC. Targeted silencing EZH2 expression, which leads to elevated FBW7 expression and then reduces MCL1 abundance, and sensitizing cancer cells to paclitaxel. According to these assumptions, this grant will explore the mechanism of EZH2 regulation of FBW7/MCL1 which conferred drug resistance in TNBC. Additionally, we design a powerful targeted plasmid, TV-siR-EZH2, strong breast cancer specific expression of siRNA to silence of EZH2, and sensitizing cancer cells to paclitaxel in TNBC. Finally, we investigate the feasibility of synergistic therapy by TV-siR-EZH2 and paclitaxel liposome in one step.

耐药是肿瘤治疗的难点与重点，大部分三阴乳腺癌病人最终会出现化疗耐药，相关机制未完全明了。FBW7/MCL1表达失调与肿瘤化疗耐药密切相关，然而FBW7上游调控机制报道较少。EZH2可通过催化组蛋白甲基化而沉默相关靶基因，参与诸多细胞进程，如肿瘤。申请人前期研究发现，EHZ2在三阴乳腺癌中高表达，病人复发转移率高，预后差。据此，提出以下假说，在三阴乳腺癌中，EZH2通过调控组蛋白甲基化而沉默FBW7，引起MCL1蓄积，从而导致肿瘤细胞耐药。靶向沉默EZH2，可促进三阴乳腺癌对紫杉醇的敏感性。基于上述假说，本课题研究EZH2调控FBW7/MCL1在三阴乳腺癌耐药中的相关机制。并以EZH2为靶点，设计靶向沉默EZH2的质粒TV-siR-EZH2，在肿瘤细胞中靶向表达针对EZH2的siRNA，沉默EZH2，恢复耐药性三阴乳腺癌细胞对紫杉醇的敏感性，并与紫杉醇协同杀伤三阴乳腺癌。

耐药是肿瘤治疗的难点与重点，大部分三阴乳腺癌病人最终会出现化疗耐药，相关机制未完全明了。FBW7/MCL1表达失调与肿瘤化疗耐药密切相关，然而FBW7上游调控机制报道较少。EZH2可通过催化组蛋白甲基化而沉默相关靶基因，参与诸多细胞进程，如肿瘤。申请研究发现，EHZ2和MCL1在三阴乳腺癌中高表达，病人复发转移率高，预后差。而在三阴乳腺癌中，下调EZH2通过调控组蛋白甲基化而沉默FBW7，引起MCL1蓄积，从而导致肿瘤细胞耐药。靶向沉默EZH2可以对三阴乳腺癌细胞的治疗有明显的作用，另外我们发现EZH2的上游PIM1抑制剂SGI-1776和紫杉醇联合治疗耐药性三阴乳腺癌，SGI-1776+Taxol组可以显著诱导肿瘤的凋亡，抑制肿瘤的体积生长，效果明显为靶点治疗三阴乳腺癌有切实的依据。