Qiao Yuan, Yu Xuechen, Zhou Bo, Zhang Kai, Huang Juyuan, Liao Jing
Department of Gynaecology and Obstetrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China.
Department of Gynaecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China.
Transl Oncol. 2022 Oct;24:101497. doi: 10.1016/j.tranon.2022.101497. Epub 2022 Jul 30.
PARP inhibitors (PARPi) are currently used as first-line therapy for advanced and recurrent ovarian cancer, but the clinical efficacy is limited by drug resistance. We aimed to investigate the role of KIAA1529 in PARPi resistance in ovarian cancer. The expression of KIAA1529 was determined in ovarian cancer cells using qRT‒PCR and western blotting. Immunohistochemistry was used to examine the expression of KIAA1529 in primary ovarian cancer and recurrent ovarian cancer tissues. The effects of KIAA1529 on PARPi resistance were evaluated by knocking down KIAA1529 expression in ovarian cancer cells and assessing cell viability by CCK8 assays, apoptosis by flow cytometry, and homologous recombination (HR) repair by immunofluorescence analysis. The interaction between KIAA1529 and RAD51 was examined by western blotting. KIAA1529 was confirmed to be expressed in all ovarian cancer cell lines, and high expression of KIAA1529 was observed in recurrent ovarian cancer tissues. Inhibiting KIAA1529 expression increased the sensitivity of ovarian cancer cells to PARPi treatment. Furthermore, KIAA1529 increased the expression of the downstream effector RAD51 via Aurora-A, and HR was restored in ovarian cancer cells. This study demonstrates that KIAA1529 regulates RAD51 expression through Aurora-A to restore HR, which confers resistance to PARPi in ovarian cancer cells. These findings could provide a novel therapeutic target to overcome PARPi resistance in ovarian cancer.
聚（ADP-核糖）聚合酶抑制剂（PARPi）目前被用作晚期和复发性卵巢癌的一线治疗药物，但临床疗效受到耐药性的限制。我们旨在研究KIAA1529在卵巢癌PARPi耐药中的作用。使用qRT-PCR和蛋白质印迹法测定卵巢癌细胞中KIAA1529的表达。免疫组织化学用于检测原发性卵巢癌和复发性卵巢癌组织中KIAA1529的表达。通过敲低卵巢癌细胞中KIAA1529的表达，并通过CCK8法评估细胞活力、流式细胞术检测细胞凋亡以及免疫荧光分析检测同源重组（HR）修复，来评估KIAA1529对PARPi耐药性的影响。通过蛋白质印迹法检测KIAA1529与RAD51之间的相互作用。证实KIAA1529在所有卵巢癌细胞系中均有表达，并且在复发性卵巢癌组织中观察到KIAA1529的高表达。抑制KIAA1529的表达可增加卵巢癌细胞对PARPi治疗的敏感性。此外，KIAA1529通过Aurora-A增加下游效应因子RAD51的表达，并使卵巢癌细胞中的HR得以恢复。本研究表明，KIAA1529通过Aurora-A调节RAD51的表达以恢复HR，从而赋予卵巢癌细胞对PARPi的耐药性。这些发现可为克服卵巢癌PARPi耐药性提供新的治疗靶点。
