Abstract

Ovarian cancer (OC) is mostly detected at late stages weighed down with metastasis, and the five-year survival rate of patients is only 30%, which dictates the necessity to develop gentler and more selectively targeted drugs that current chemotherapeutic agents. The search for factors that can influence on the activity of the PD-1/PD-L1 immune checkpoint signaling pathway in tumors is relevant, and microRNAs (miRNAs) play an important role in it. Over the past 5 years, only a few miRNAs (miR-34a, miR-145, and miR-424), which have a regulatory effect on the PD-1/PD-L1 system in OC patients, have been discovered. In present work, the methylation levels of 13 miRNA genes in 26 primary tumors and 19 peritoneal metastases of OC patients were determined and compared with the level of the soluble form of PD-L1 (sPD-L1) in the blood plasma of the same patients. It was shown that the methylation levels of five miRNA genes (MIR124-2, MIR34B/C, MIR9-1, MIR9-3, and MIR339) in tumors are in direct correlation with the sPD-L1 level in the blood plasma. In addition, when analyzing these five genes, a significant association of the methylation level of the MIR9-1 gene with a decrease in the three-year relapse-free survival, and a trend for decrease in the three-year survival rate with the methylation level of the MIR124-2 gene of OC patients were determined. Thus, the first data suggesting the role of inhibitors of the sPD-L1 immune checkpoint for five miRNAs (miR-124, miR-34b, miR-34c, miR-9, miR-339) and the possibility of using hypermethylated MIR9-1 and, presumably, MIR124-2 genes as independent prognostic markers of poor disease-free survival in OC patients were obtained.

中文翻译：

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新型miRNA作为PD-1 / PD-L1免疫检查点的潜在调节剂以及MIR9-1和MIR124-2甲基化在卵巢癌中的预后价值

摘要

卵巢癌（OC）大多是在转移较重的晚期阶段检测到的，患者的五年生存率仅为30％，这表明有必要开发出比目前化疗药物更温和，更有针对性的药物。寻找可能影响肿瘤中PD-1 / PD-L1免疫检查点信号通路活性的因素非常重要，microRNA（miRNA）在其中发挥着重要作用。在过去的5年中，仅发现了少数对OC患者的PD-1 / PD-L1系统具有调节作用的miRNA（miR-34a，miR-145和miR-424）。在目前的工作中，确定了OC患者的26个原发肿瘤和19个腹膜转移中的13个miRNA基因的甲基化水平，并将其与同一患者血浆中PD-L1可溶性形式（sPD-L1）的水平进行比较。结果表明，五个miRNA基因的甲基化水平（肿瘤中的MIR124-2，MIR34B / C，MIR9-1，MIR9-3和MIR339）与血浆中的sPD-L1水平直接相关。此外，在分析这五个基因时，MIR9-1基因的甲基化水平与三年无复发生存率的下降以及三年生存率与甲基化率下降的趋势之间存在显着关联确定OC患者的MIR124-2基因水平。因此，第一个数据提示了sPD-L1免疫检查点抑制剂对五个miRNA（miR-124，miR-34b，miR-34c，miR-9，miR-339）的作用，以及使用超甲基化MIR9-1的可能性并推测获得了MIR124-2基因作为OC患者无病生存率低的独立预后标记。