Yu Rao, Zhang Hao, Wang Rong, Xiao Lin
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Oncol Lett. 2022 Oct 11;24(6):423. doi: 10.3892/ol.2022.13543. eCollection 2022 Dec.
Epithelial ovarian cancer (EOC) is the most common cause of gynecological cancer-associated mortality. Cisplatin is one of the most effective chemotherapeutic drugs used in EOC; however, its use can lead to relapse due to cisplatin resistance. MYCN sensitizes neuroblastoma to undergo cisplatin-induced apoptosis. However, to the best of our knowledge, there have been no studies to date on the association between MYCN and cisplatin resistance in EOC. Therefore, the present study assessed this association. Datasets from The Cancer Genome Atlas database were used. The overall survival (OS) of patients receiving platin-based therapy was analyzed using Kaplan-Meier Plotter software. RNA sequencing data of 300 patients with EOC were downloaded from cBioportal. The co-expressed genes were subjected to 'Kyoto Encyclopedia of Genes and Genomes' analysis using DAVID software. For gene set enrichment analysis, the expression matrix was separated according to the median expression of MYCN, which was selected for hallmark gene set enrichment. Immunohistochemistry was used to assess MYCN expression in EOC tissue. Western blotting was used to evaluate MYCN, p53, Bax and Bcl-2 protein expression levels in EOC cells. Cell viability and apoptosis were assessed using Cell Counting Kit-8 and flow cytometry, respectively. The results demonstrated that MYCN upregulation was associated with increased cisplatin sensitivity and prolonged OS of patients with EOC and patients receiving platin-based therapy. Cisplatin downregulated MYCN expression in cisplatin-sensitive, but not resistant, EOC cells. The genes co-expressed with MYCN were primarily involved in pathways involved in 'chemotherapeutic resistance' and 'apoptosis'. MYCN enriched the apoptosis and p53 signaling pathways in hallmark gene sets. Cells in which MYCN was knocked down demonstrated significantly increased cisplatin resistance; however, MYCN overexpression in cisplatin-resistant cells restored cisplatin sensitivity. Collectively, the present study demonstrated that MYCN downregulation promoted cisplatin resistance by suppressing cisplatin-induced apoptosis in EOC.
上皮性卵巢癌（EOC）是妇科癌症相关死亡的最常见原因。顺铂是用于EOC的最有效的化疗药物之一；然而，由于顺铂耐药，其使用可能导致复发。MYCN使神经母细胞瘤对顺铂诱导的凋亡敏感。然而，据我们所知，迄今为止尚无关于EOC中MYCN与顺铂耐药之间关联的研究。因此，本研究评估了这种关联。使用了来自癌症基因组图谱数据库的数据集。使用Kaplan-Meier Plotter软件分析接受铂类疗法患者的总生存期（OS）。从cBioportal下载了300例EOC患者的RNA测序数据。使用DAVID软件对共表达基因进行“京都基因与基因组百科全书”分析。对于基因集富集分析，根据MYCN的中位表达将表达矩阵分开，选择MYCN进行标志性基因集富集。免疫组织化学用于评估EOC组织中MYCN的表达。蛋白质印迹法用于评估EOC细胞中MYCN、p53、Bax和Bcl-2蛋白的表达水平。分别使用细胞计数试剂盒-8和流式细胞术评估细胞活力和凋亡。结果表明，MYCN上调与EOC患者及接受铂类疗法患者的顺铂敏感性增加和OS延长相关。顺铂下调了顺铂敏感而非耐药的EOC细胞中MYCN的表达。与MYCN共表达的基因主要参与“化疗耐药”和“凋亡”相关途径。MYCN在标志性基因集中富集了凋亡和p53信号通路。敲低MYCN的细胞显示顺铂耐药性显著增加；然而，顺铂耐药细胞中MYCN的过表达恢复了顺铂敏感性。总体而言，本研究表明，MYCN下调通过抑制EOC中顺铂诱导的凋亡促进顺铂耐药。
