CD147调节FOXM1泛素化降解参与卵巢癌顺铂耐药细胞DNA损伤抵抗的功能及机制研究

The therapeutic principle of cisplatin is that its formation of DNA adducts promotes the DNA damage leading to the cell death. The enhancement of repair ability of DNA damage and survival ability are the key mechanisms of cisplatin resistance in ovarian cancer cells. Many researches and our data have shown that the drug target molecule of CD147 plays an important role on cisplatin resistant cells, and has the function of DNA damage repair and anti-apoptosis. We also found that FOXM1 was phosphorylated by GSK3β and degraded in an ubiquitin-dependent manner. FOXM1 not only regulates various DNA damage repair molecules, but also probably participates in the regulation of DNA damage repair protein ERCC1 and anti-apoptotic protein BCL-2 in ovarian cancer cells. Because GSK3β is inhibited by the downstream signal PI3K/AKT of CD147, we speculated that CD147 may inhibit FoxM1 ubiquitination and degradation through PI3k/Akt-GSK3β signaling pathway, thereby promoting DNA damage repair and anti-apoptotic effect. The aim of this study is to establish an drug resistance PDX model of ovarian cancer, and to explore the role and mechanism of CD147 molecule in promoting resistance of DNA damage in drug-resistant ovarian cancer cells from cell and animal level. This project will provide a new idea and possibility of drug combination in ovarian cancer therapy.

顺铂的治疗原理是与DNA形成加合物引起DNA损伤造成细胞死亡。DNA损伤修复及损伤后存活能力的增强是卵巢癌细胞顺铂耐药的关键机制。多项研究及申请人的数据提示药靶CD147分子可能在顺铂耐药细胞中发挥DNA损伤修复和抗凋亡的功能。申请人发现FOXM1受到GSK3β的磷酸化修饰而增强了泛素化降解过程，FOXM1除了调节多种DNA损伤修复分子外，还可能参与卵巢癌细胞DNA损伤修复蛋白ERCC1、抗凋亡蛋白BCL-2的调节。由于GSK3β受到CD147的下游信号PI3K/AKT的抑制，申请人推测CD147可能通过PI3k/Akt-GSK3β信号通路抑制FoxM1的泛素化降解，从而促进DNA损伤修复及损伤后的抗凋亡作用。本课题拟构建卵巢癌耐药PDX模型，从细胞及动物水平探讨CD147分子在卵巢癌耐药细胞中促进DNA损伤抵抗的作用及机制，为卵巢癌提供新的联合用药方案及治疗思路。

CD147是一种跨膜糖蛋白，在包括卵巢癌在内的许多人类癌症中高度表达。靶向CD147的抗体药物利卡汀(Licartin®)已获得中国食品药品监督管理局(FDA)批准，并进入临床治疗。一些研究表明CD147在肿瘤耐药中发挥作用，但其分子机制尚不清楚。本研究旨在探讨CD147在卵巢癌顺铂耐药中的作用及机制。我们发现CD147通过激活卵巢癌细胞中PI3k/Akt-GSK3β通路调控FOXM1的泛素化和降解，并进一步调控DNA损伤修复基因的表达。CUT&Tag-seq数据显示，FOXM1可以直接结合到一些DNA损伤修复(DDR)基因的启动子区域，如BRIP1、RRM1、FEN1、RAD50和PMS2，从而调节它们的转录。在体内和体外实验中，抗CD147的siRNA降低了FOXM1和DDR基因的表达，提高了卵巢癌顺铂治疗效果。我们的研究结果显示了一种新的顺铂耐药机制，并提示顺铂联合CD147抑制是治疗顺铂耐药卵巢癌的一种前瞻性治疗方案。