细胞周期蛋白PRC1调控同源重组修复促进卵巢癌PARP抑制剂耐药的机制研究

PARP抑制剂（PARPi）耐药是当前卵巢癌治疗的一大难点问题。前期研究发现：细胞周期蛋白PRC1过表达可以导致卵巢癌患者的不良预后，并且PRC1在PARPi非敏感患者中过表达。卵巢癌细胞干扰PRC1后，癌细胞对PARPi的敏感性增加，可能与降低癌细胞的同源重组修复能力有关。进一步研究发现：PRC1与细胞周期蛋白CENPE的表达存在高度一致性，CENPE能与多种细胞周期检查点蛋白相结合，协调检查点的信号级连反应，参与DNA损伤修复。据此推测，在卵巢癌中，过表达的PRC1与CENPE存在一定的相互作用，激活细胞周期检查点，增强癌细胞的同源重组修复功能，从而导致PARPi耐药。本课题拟采用中性彗星实验、DNA损伤同源重组修复检测系统I-SecI-HR、Co-IP、荧光共振能量转移技术及动物实验等，探索PRC1导致卵巢癌PARPi耐药的分子机制，为卵巢癌治疗提供新的理论依据。

PARP inhibitor ( PARPi ) resistance is a difficult problem in the treatment of ovarian cancer. Previous studies found that over-expression of PRC1 could lead to poor prognosis of ovarian cancer patients, and PRC1 was over-expressed in PARPi non-sensitive patients. Knockdown of PRC1 in ovarian cancer cells could increase the sensitivity to PARPi, which might be related to the reduced ability of homologous recombination repair. Further study showed that PRC1 was highly consistent with the expression of cell cycle protein CENPE. CENPE could combine with a variety of cell cycle checkpoint proteins, coordinate the signal cascade reaction and participate in DNA damage repair. It is speculated that there is a certain interaction between PRC1 and CENPE in ovarian cancer, which activates cell cycle checkpoints, promotes homologous recombination repair function of cancer cells, and leads to PARPi resistance. In this study, neutral comet assay, I-SecI-HR system, Co-IP, fluorescence resonance energy transfer technology and animal experiments will be used to explore the molecular mechanism of PARPi resistance induced by PRC1 in ovarian cancer and provide new theoretical basis for the treatment of ovarian cancer.