Department of Obstetrics and Gynecology, Shanghai General Hospital of Nanjing Medical University, Shanghai 200080, P.R. China.
Department of Oncology, Shanghai General Hospital of Nanjing Medical University, Shanghai 200080, P.R. China.
Int J Mol Med. 2019 Jan;43(1):256-266. doi: 10.3892/ijmm.2018.3958. Epub 2018 Oct 25.
The present study aimed to identify shared microRNAs (miRNAs) in ovarian cancer (OC) cells and their exosomes using microarray data (accession number GSE103708) available from the Gene Expression Omnibus database, including exosomal samples from 13 OC cell lines and 3 normal ovarian surface epithelial cell lines, and their original cell samples. Differentially expressed miRNAs (DE‑miRNAs) were identified using the Linear Models for Microarray data method, and mRNA targets of DE‑miRNAs were predicted using the miRWalk2 database. The potential functions of target genes were analyzed using Database for Annotation, Visualization and Integrated Discovery and intersected with known OC‑associated pathways downloaded from the Comparative Toxicogenomics Database. The associations between crucial miRNAs and target genes, and their clinical associations, were validated using data from The Cancer Genome Atlas. As a result, 16 upregulated and 6 downregulated DE‑miRNAs were shared in OC cell lines and their exosomes compared with normal controls. The target genes of 11 common DE‑miRNAs were predicted. Among these DE‑miRNAs, a low expression of homo sapiens (hsa)‑miR‑145‑5p was significantly correlated with a poor prognosis and higher stages. Although 91 target genes were predicted for hsa‑miR‑145‑5p, only 4 genes [connective tissue growth factor (CTGF), myotubularin‑related protein 14, protein phosphatase 3 catalytic subunit alpha and suppressor of cytokine signaling 7] were suggested as risk factors for prognosis. The subsequent Pearson's correlation analysis validated a significant negative correlation between hsa‑miR‑145‑5p and CTGF (r=‑0.1126, P=0.02188). According to the results of the functional analysis, CTGF is involved in the Hippo signaling pathway (hsa04390). In conclusion, decreased expression of hsa‑miR‑145 in OC and OC‑derived exosomes may be a crucial biomarker for the diagnosis and treatment of OC.
本研究旨在通过分析基因表达综合数据库中可用的微阵列数据（注册号 GSE103708），包括 13 种卵巢癌细胞系和 3 种正常卵巢表面上皮细胞系及其原代细胞样本中的外泌体样本，来鉴定卵巢癌细胞和其外泌体中的共享 microRNAs（miRNAs）。使用线性模型分析微阵列数据的方法鉴定差异表达的 miRNAs（DE-miRNAs），并使用 miRWalk2 数据库预测 DE-miRNAs 的 mRNA 靶标。使用数据库进行注释、可视化和综合发现（Database for Annotation, Visualization and Integrated Discovery）分析靶基因的潜在功能，并与从比较毒理学基因组数据库（Comparative Toxicogenomics Database）下载的已知与 OC 相关的途径进行交叉分析。使用癌症基因组图谱（The Cancer Genome Atlas）的数据验证关键 miRNA 和靶基因之间的关联及其临床关联。结果显示，与正常对照相比，卵巢癌细胞系及其外泌体中共有 16 个上调和 6 个下调的 DE-miRNAs。预测到 11 个共同 DE-miRNA 的靶基因。在这些 DE-miRNAs 中，homo sapiens（hsa）-miR-145-5p 的低表达与不良预后和较高分期显著相关。尽管 hsa-miR-145-5p 预测有 91 个靶基因，但只有 4 个基因[结缔组织生长因子（connective tissue growth factor，CTGF）、肌管相关蛋白 14、蛋白磷酸酶 3 催化亚基 α 和细胞因子信号抑制因子 7]被认为是预后的危险因素。随后的 Pearson 相关性分析验证了 hsa-miR-145-5p 与 CTGF 之间存在显著的负相关性（r=-0.1126，P=0.02188）。根据功能分析的结果，CTGF 参与 Hippo 信号通路（hsa04390）。综上所述，OC 和 OC 衍生的外泌体中 hsa-miR-145 的表达降低可能是 OC 诊断和治疗的重要生物标志物。
