MUS81 Inhibition Increases the Sensitivity to Therapy Effect in Epithelial Ovarian Cancer via Regulating CyclinB Pathway
MUS81 Inhibition Increases the Sensitivity to Therapy Effect in Epithelial Ovarian Cancer via Regulating CyclinB Pathway
复制标题
MUS81 抑制通过调节 CyclinB 通路提高上皮性卵巢癌治疗效果的敏感性
DOI：
10.7150/jca.30818
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发表时间：
2019
影响因子：
3.9
通讯作者：
Guo Lin
中科院分区：
文献类型：
--
作者：
Zhong Ailing;Zheng Hui;Zhang Hongqin;Sun Jiajun;Shen Jiabin;Deng Minjie;Chen Miaomiao;Lu Renquan;Guo Lin
MUS 81是DNA双链损伤后参与同源重组（HR）修复的关键核酸内切酶。结构特异性核酸内切酶（Structure-specific endonucleases，SSE）在DNA的复制、修复和转录中起着至关重要的作用，并且对于维持DNA的二级结构也很重要;因此，必须精确地控制它们的活性以确保基因组的稳定性。我们先前描述了基于蛋白质微阵列分析的MUS 81表达与CyclinB表达显著相关。细胞周期蛋白B是一种细胞周期调节蛋白，其通过诱导G2/M期阻滞、促进细胞凋亡参与DNA损伤修复检查点的激活，并通过诱导核降解参与化疗药物敏感性的调节，如免疫荧光测定所示。在这项研究中，使用慢病毒介导的RNAi产生MUS 81下调的细胞。我们的研究结果表明，MUS 81表达的抑制激活了CHK 1和CyclinB信号通路，并在体外和体内使卵巢癌细胞对X射线和奥拉帕尼治疗敏感。MUS 81可能是上皮性卵巢癌（EOC）潜在的治疗靶点。
MUS81 is a key endonuclease involved in homologous recombination (HR) repair after DNA double-strand damage. Structure-specific endonucleases (SSEs) plays a crucial role in DNA replication, repair and transcription, and SSEs are also important for maintaining the secondary structure of DNA; therefore, their activity must be precisely controlled to ensure genome stability. We previously described that MUS81 expression was significantly correlated with CyclinB expression based on protein microarray analysis. CyclinB is a cell-cycle regulatory protein that has been shown to be involved in the activation of DNA damage repair checkpoints by inducing G2/M phase arrest, promoting apoptosis, and participating in the regulation of chemotherapeutic drug sensitivity by inducing nuclear degradation, as shown by immunofluorescence assays. In this study, MUS81-downregulated cells were generated using lentivirus-mediated RNAi. Our results demonstrated that the inhibition of MUS81 expression activated the CHK1 and CyclinB signaling pathways and sensitized ovarian cancer cells to X-ray and Olaparib treatment both in vitro and in vivo. MUS81 may be a potential therapeutic target for epithelial ovarian cancer (EOC).