Ramírez-Coronel Andrés Alexis, Rostami Amirabbas, Younus Laith A, Arias Gonzáles José Luis, Lafta Methaq Hadi, Amin Ali H, Saadoon Mohammed Abdulkadhim, Salman Hayder Mahmood, Bahrami Abolfazl, Feilei Rossa, Akhavan-Sigari Reza
Epidemiology and Biostatistics Group, Research Group in Educational Statistics, National University of Education (UNAE), Azogues 030102, Ecuador.
Azogues Campus Nursing Career, Health and Behavior Research Group (HBR), Psychometry and Ethology Laboratory, Catholic University of Cuenca, Cuenca 010109, Ecuador.
Biomedicines. 2023 Mar 13;11(3):879. doi: 10.3390/biomedicines11030879.
Recurrent pregnancy loss (RPL) occurs in approximately 5% of women. Despite an abundance of evidence, the molecular mechanism of RPL's pathology remains unclear. Here, we report the protective role of polo-like kinase 1 (PLK1) during RPL. We aimed to construct an RPL network utilizing GEO datasets and identified hub high-traffic genes. We also investigated whether the expressions of PLK1 were altered in the chorionic villi collected from women with RPL compared to those from healthy early pregnant women. Gene expression differences were evaluated using both pathway and gene ontology (GO) analyses. The identified genes were validated using in vivo and in vitro models. Mice with PLK1-overexpression and PLK1-knockdown in vitro models were produced by transfecting certain plasmids and si-RNA, respectively. The apoptosis in the chorionic villi, mitochondrial function, and NF-κB signaling activity was evaluated. To suppress the activation of PLK1, the PLK1 inhibitor BI2536 was administered. The HTR-8/SVneo and JEG-3 cell lines were chosen to establish an RPL model in vitro. The NF-κB signaling, Foxo signaling, PI3K/AKT, and endometrial cancer signaling pathways were identified via the RPL regulatory network. The following genes were identified: as hub high-traffic gene and , , , , , , , , , , , , and . Clinical samples were examined, and the results demonstrated that RPL patients had tissues with decreased PLK1 expression in comparison to women with normal pregnancies ( < 0.01). In vitro, PLK1 knockdown induced the NF-κB signaling pathway and apoptosis activation while decreasing cell invasion, migration, and proliferation ( < 0.05). Furthermore, the in vivo model proved that cell mitochondrial function and chorionic villi development are both hampered by PLK1 suppression. Our findings revealed that the PLK1/TRAF2/NF-κB axis plays a crucial role in RPL-induced chorionic villi dysfunction by regulating mitochondrial dynamics and apoptosis and might be a potential therapeutic target in the clinic.
复发性流产（RPL）在约5%的女性中发生。尽管有大量证据，但RPL病理的分子机制仍不清楚。在此，我们报告了polo样激酶1（PLK1）在RPL中的保护作用。我们旨在利用GEO数据集构建一个RPL网络，并识别枢纽高流量基因。我们还研究了与健康早孕女性相比，RPL女性绒毛膜绒毛中PLK1的表达是否发生改变。使用通路分析和基因本体（GO）分析来评估基因表达差异。使用体内和体外模型对鉴定出的基因进行验证。分别通过转染特定质粒和小干扰RNA（si-RNA）构建PLK1过表达小鼠和体外模型中的PLK1敲低小鼠。评估绒毛膜绒毛中的细胞凋亡、线粒体功能和NF-κB信号活性。为了抑制PLK1的激活，给予PLK1抑制剂BI2536。选择HTR-8/SVneo和JEG-3细胞系建立体外RPL模型。通过RPL调控网络鉴定出NF-κB信号通路、Foxo信号通路、PI3K/AKT和子宫内膜癌信号通路。鉴定出以下基因作为枢纽高流量基因以及……（此处原文未完整列出基因名称）。对临床样本进行检测，结果表明与正常妊娠女性相比，RPL患者组织中PLK1表达降低（P<0.01）。在体外，PLK1敲低诱导NF-κB信号通路和细胞凋亡激活，同时降低细胞侵袭、迁移和增殖能力（P<0.05）。此外，体内模型证明PLK1抑制会阻碍细胞线粒体功能和绒毛膜绒毛发育。我们的研究结果表明，PLK1/TRAF2/NF-κB轴通过调节线粒体动力学和细胞凋亡在RPL诱导的绒毛膜绒毛功能障碍中起关键作用，可能是临床上一个潜在的治疗靶点。
