竞争内源性 RNA 网络揭示了具有早期乳腺癌诊断和预后价值的新型 lncRNA、miRNA 和 mRNA 生物标志物。
A Competing Endogenous RNA Network Reveals Novel lncRNA, miRNA and mRNA Biomarkers With Diagnostic and Prognostic Value for Early Breast Cancer.
机构信息
Department of Breast Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou of Jiangxi Province, China.
出版信息
Technol Cancer Res Treat. 2020 Jan-Dec;19:1533033820983293. doi: 10.1177/1533033820983293.
BACKGROUND
This study aims to reveal early breast cancer (BC) specific competing endogenous RNA (ceRNA) network through the expression profiles of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and mRNAs.
METHODS
Based on The Cancer Genome Atlas (TCGA), we obtained the differentially expressed mRNAs, miRNAs, and lncRNAs (DEmRNAs, DEmiRNAs and DElncRNAs) between early BC and normal samples. The lncRNA-miRNA-mRNA interaction network was constructed using Cytoscape. Functional enrichment were performed using GeneCoDis3. The expression of selected genes were validated by qRT-PCR. Based on the published dataset, we validated the result of TCGA integration analysis. The diagnostic and prognostic value of candidate genes was evaluated by ROC curve analysis and survival analysis, respectively.
RESULTS
Totally, 1207 DEmRNAs, 194 DElncRNAs and 37 DEmiRNAs were obtained. Functional enrichment analysis results showed that all of DEmRNAs were enriched in pathway of cytokine-cytokine receptor interaction, PPAR signaling pathway and pathways in cancer. The DEmRNA-DEmiRNA-DElncRNA interaction network in early BC was consisted of 23 DEmiRNAs, 95 DElncRNAs and 309 DEmRNAs. Among ceRNA network, IL-6-hsa-miR-182-5p-ADAMTS9-AS1 interactions, LIFR-hsa-miR-21-5p-ADAMTS9-AS1 interactions and MMP1/MMP11-hsa-miR-145-5p-CDKN2B-AS1 interactions were speculated to involve in the development of early BC. The qRT-PCR results were consistent with our integrated analysis. Except for ADAMTS9-AS1 and CDKN2B-AS1, expression of the others results in the Gene Expression Omnibus (GEO) dataset were generally consistent with TCGA integrated analysis. The area under curve (AUC) of the ADAMTS9-AS1, CDKN2B-AS1, IL-6, MMP11, hsa-miR-145-5p and hsa-miR-182-5p were 0.947, 0.862, 0.842, 0.993, 0.960 and 0.944, and the specificity and sensitivity of the 6 biomarkers were 83.4% and 95.6%, 72.2% and 90.3%, 80.1% and 74.3%, 96.2% and 96.5%, 90.1% and 92.3%, and 88.7% and 90.4%, respectively. In addition, IL-6 had potential prognostic value for early BC.
CONCLUSION
These findings may provide novel insights into the lncRNA-miRNA-mRNA network and uncover potential therapeutic targets in early BC.
背景
本研究旨在通过 microRNAs (miRNAs)、长非编码 RNA (lncRNAs) 和信使 RNA (mRNAs) 的表达谱来揭示早期乳腺癌 (BC) 特定的竞争内源性 RNA (ceRNA) 网络。
方法
基于癌症基因组图谱 (TCGA)，我们获得了早期 BC 与正常样本之间差异表达的 mRNAs、miRNAs 和 lncRNAs (DEmRNAs、DEmiRNAs 和 DElncRNAs)。使用 Cytoscape 构建 lncRNA-miRNA-mRNA 相互作用网络。使用 GeneCoDis3 进行功能富集分析。通过 qRT-PCR 验证选定基因的表达。基于已发表的数据集，我们验证了 TCGA 整合分析的结果。通过 ROC 曲线分析和生存分析分别评估候选基因的诊断和预后价值。
结果
总共获得了 1207 个 DEmRNAs、194 个 DElncRNAs 和 37 个 DEmiRNAs。功能富集分析结果表明，所有的 DEmRNAs 都富集在细胞因子-细胞因子受体相互作用、PPAR 信号通路和癌症途径中。早期 BC 的 DEmRNA-DEmiRNA-DElncRNA 相互作用网络由 23 个 DEmiRNAs、95 个 DElncRNAs 和 309 个 DEmRNAs 组成。在 ceRNA 网络中，IL-6-hsa-miR-182-5p-ADAMTS9-AS1 相互作用、LIFR-hsa-miR-21-5p-ADAMTS9-AS1 相互作用和 MMP1/MMP11-hsa-miR-145-5p-CDKN2B-AS1 相互作用被推测与早期 BC 的发生有关。qRT-PCR 结果与我们的整合分析一致。除了 ADAMTS9-AS1 和 CDKN2B-AS1，在基因表达综合数据库 (GEO) 数据集的其他结果的表达通常与 TCGA 整合分析一致。ADAMTS9-AS1、CDKN2B-AS1、IL-6、MMP11、hsa-miR-145-5p 和 hsa-miR-182-5p 的曲线下面积 (AUC) 分别为 0.947、0.862、0.842、0.993、0.960 和 0.944，6 种生物标志物的特异性和敏感性分别为 83.4%和 95.6%、72.2%和 90.3%、80.1%和 74.3%、96.2%和 96.5%、90.1%和 92.3%和 88.7%和 90.4%。此外，IL-6 对早期 BC 具有潜在的预后价值。
结论
这些发现可能为 lncRNA-miRNA-mRNA 网络提供新的见解，并揭示早期 BC 中的潜在治疗靶点。
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