Zhang P, He M, Zeng Y, Cai X
Department of Gynecology, Chongqing Health Center for Women and Children(Women and Children's Hospital of Chongqing Medical University), Chongqing 401147, China.
Department of Obstetrics and Gynecology, First Affiliated Hospital of Army Medical University, Chongqing 400038, China.
Nan Fang Yi Ke Da Xue Xue Bao. 2023 Jan 20;43(1):8-16. doi: 10.12122/j.issn.1673-4254.2023.01.02.
To investigate the correlation of the potential functional microRNA (miRNA)-mRNA regulatory network with recurrence of high-grade serous ovarian carcinoma (HGSOC) and its biological significance.
This study was performed based on the data of 354 patients with HGSOC from the Cancer Genome Atlas database. In these patients, HGSOC was divided into different subtypes based on the pathways identified by GO analysis, and the correlations of the subtypes with HGSOC recurrence and differentially expressed miRNAs and mRNAs were assessed. Two relapse-related datasets were identified using the Gene Set Enrichment (GSE) database, from which the differentially expressed miRNAs were identified by intersection with the TCGA data. The target genes of these miRNAs were predicted using miRWalk 2.0 database, and these common differentially expressed miRNAs and mRNAs were used to construct the key miRNA-mRNA network associated with HGSOC recurrence. The expression of miR-506-3p and SNAI2 in two ovarian cancer cell lines was detected using RT-qPCR and Western blotting, and their targeted binding was verified using a double luciferase assay. The effect of miR-506-3p expression modulation on ovarian cancer cell migration was detected using scratch assay and Transwell assay.
We screened 303 GO terms of HGSOC-related pathways and identified two HGSOC subtypes (C1 and C2). The subtype C1 was associated with a significantly higher recurrence rate than C2. The differentially expressed genes between C1 and C2 subtypes were mainly enriched in epithelial-mesenchymal transition (EMT). Five miRNAs were identified as potential regulators of EMT, and a total of 41 target genes were found to be involved in the differential expressions of EMT pathway between C1 and C2 subtypes. The key miRNA-mRNA network associated with HGSOC recurrence was constructed based on these 5 miRNAs and 41 mRNAs. MiR-506-3p was confirmed to bind to SNAI2, and up-regulation of miR-506-3p significantly inhibited SNAI2 expression and reduced migration and invasion of SKOV3 and CAOV3 cells ( < 0.05), while miR-506-3p knockdown produced the opposite effects ( < 0.05).
MiR-506-3p and SNAI2 are the key molecules associated with HGSOC recurrence. MiR-506-3p may affect EMT of ovarian cancer cells by regulating cell migration and invasion via SNAI2, and its expression level has predictive value for HGSOC recurrence.
探讨潜在功能性微小RNA（miRNA）-信使核糖核酸（mRNA）调控网络与高级别浆液性卵巢癌（HGSOC）复发的相关性及其生物学意义。
本研究基于来自癌症基因组图谱数据库的354例HGSOC患者的数据进行。在这些患者中，根据基因本体（GO）分析确定的途径将HGSOC分为不同亚型，并评估这些亚型与HGSOC复发以及差异表达的miRNA和mRNA的相关性。使用基因集富集（GSE）数据库鉴定了两个与复发相关的数据集，通过与TCGA数据交叉分析从中鉴定出差异表达的miRNA。使用miRWalk 2.0数据库预测这些miRNA的靶基因，并利用这些共同的差异表达miRNA和mRNA构建与HGSOC复发相关的关键miRNA-mRNA网络。采用逆转录定量聚合酶链反应（RT-qPCR）和蛋白质免疫印迹法检测两种卵巢癌细胞系中miR-506-3p和SNAI2的表达，并通过双荧光素酶报告基因检测验证它们的靶向结合。采用划痕实验和Transwell实验检测miR-506-3p表达调控对卵巢癌细胞迁移的影响。
我们筛选出303个与HGSOC相关途径的GO词条，并鉴定出两种HGSOC亚型（C1和C2）。C1亚型的复发率显著高于C2亚型。C1和C2亚型之间的差异表达基因主要富集在上皮-间质转化（EMT）过程中。鉴定出5种miRNA作为EMT的潜在调节因子，共发现41个靶基因参与C1和C2亚型之间EMT途径的差异表达。基于这5种miRNA和41种mRNA构建了与HGSOC复发相关的关键miRNA-mRNA网络。证实miR-506-3p与SNAI2结合，上调miR-506-3p显著抑制SNAI2表达，并降低SKOV3和CAOV3细胞的迁移和侵袭能力（P<0.05），而敲低miR-506-3p则产生相反的效果（P<0.05）。
miR-506-3p和SNAI2是与HGSOC复发相关的关键分子。miR-506-3p可能通过SNAI2调节细胞迁移和侵袭来影响卵巢癌细胞的EMT，其表达水平对HGSOC复发具有预测价值。
