构建并综合分析肿瘤-淋巴结-转移（TNM）Ⅰ期肝癌中的竞争内源性 RNA 网络。
Construction and Comprehensive Analyses of a Competing Endogenous RNA Network in Tumor-Node-Metastasis Stage I Hepatocellular Carcinoma.
机构信息
Department of Liver Disease, The Second Hospital of Nanjing, Medical School, Southeast University, Nanjing 210003, China.
Department of Hepatology, Infectious Diseases Hospital Affiliated with Soochow University, Suzhou 215000, China.
出版信息
Biomed Res Int. 2020 Feb 11;2020:5831064. doi: 10.1155/2020/5831064. eCollection 2020.
BACKGROUND
Long noncoding RNAs (lncRNAs) can function as competing endogenous RNAs (ceRNAs) and interact with microRNAs (miRNAs) to regulate target gene expression, which can greatly influence tumor development and progression. Different tumor-node-metastasis (TNM) stages of hepatocellular carcinoma (HCC) defined by the American Joint Committee on Cancer (AJCC) have different clinical results. Our purpose was to comprehensively analyze differentially expressed (DE) lncRNAs, miRNAs, and mRNAs in stage I HCC and identify prognosis-associated RNAs.
METHODS
RNA-seq data were obtained from The Cancer Genome Atlas (TCGA) database. A stage I HCC-associated miRNA-lncRNA-mRNA network was constructed. Next, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analyses of ceRNA-associated DEmRNAs were performed using Database for Annotation, Visualization, and Integrated Discovery (DAVID) 6.8 and Clusterprofile in the R package. The protein-protein interaction (PPI) network of the above mRNAs was then constructed using STRING. Finally, the association between lncRNAs and mRNAs in the ceRNA network and prognosis of patients was further analyzed. Linear regression analysis of the above lncRNAs and mRNAs associated with overall survival was performed.
RESULTS
After a comparison between HCC and adjacent nontumor tissues, 778 lncRNAs, 1608 mRNAs, and 102 miRNAs that were abnormally expressed were identified. The ceRNA network was composed of 56 DElncRNAs, 14 DEmiRNAs, and 30 DEmRNAs. Functional analysis results showed that 30 DEmRNAs were enriched in 14 GO biological process categories and 6 KEGG categories (false discovery rate (FDR) < 0.05). A PPI network was composed of 22 nodes and 58 edges. We detected 4 DElncRNAs (BPESC1, AC061975.6, AC079341.1, and CLLU1) and 6 DEmRNAs (CEP55, E2F1, E2F7, EZH2, G6PD, and SLC7A11) that had significant influences on the overall survival (OS) of stage I HCC patients ( < 0.05). lncRNA BPESC1 was positively correlated with mRNA CEP55 via miR-424, and lncRNA AC061975.6 was positively correlated with mRNA E2F1 via miR-519d.
CONCLUSION
Our study identified novel lncRNAs and mRNAs that were associated with the progression and prognosis of stage I HCC and further investigated the regulatory mechanism of lncRNA-mediated ceRNAs in the development of stage I HCC.
背景
长非编码 RNA（lncRNA）可以作为竞争性内源 RNA（ceRNA）发挥作用，并与 microRNA（miRNA）相互作用，调节靶基因的表达，这极大地影响肿瘤的发生和发展。美国癌症联合委员会（AJCC）定义的不同肝癌（HCC）肿瘤-淋巴结-转移（TNM）分期具有不同的临床结果。我们的目的是全面分析 I 期 HCC 中差异表达的 lncRNA、miRNA 和 mRNA，并鉴定与预后相关的 RNA。
方法
从癌症基因组图谱（TCGA）数据库中获取 RNA-seq 数据。构建 I 期 HCC 相关的 miRNA-lncRNA-mRNA 网络。接下来，使用数据库注释、可视化和综合发现（DAVID）6.8 和 R 包中的 Clusterprofile 对 ceRNA 相关 DEmRNAs 进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集途径分析。然后使用 STRING 构建上述 mRNAs 的蛋白质-蛋白质相互作用（PPI）网络。最后，进一步分析 ceRNA 网络中 lncRNA 和 mRNAs 与患者预后的关系。对与总生存期相关的上述 lncRNA 和 mRNAs 进行线性回归分析。
结果
在 HCC 与相邻非肿瘤组织之间进行比较后，鉴定出 778 个异常表达的 lncRNA、1608 个 mRNA 和 102 个 miRNA。ceRNA 网络由 56 个差异表达的 lncRNA、14 个差异表达的 miRNA 和 30 个差异表达的 mRNA 组成。功能分析结果表明，30 个 DEmRNAs 富集在 14 个 GO 生物过程类别和 6 个 KEGG 类别（错误发现率（FDR）<0.05）。一个 PPI 网络由 22 个节点和 58 个边组成。我们检测到 4 个差异表达的 lncRNA（BPESC1、AC061975.6、AC079341.1 和 CLLU1）和 6 个差异表达的 mRNA（CEP55、E2F1、E2F7、EZH2、G6PD 和 SLC7A11）对 I 期 HCC 患者的总体生存（OS）有显著影响（<0.05）。lncRNA BPESC1 通过 miR-424 与 mRNA CEP55 呈正相关，lncRNA AC061975.6 通过 miR-519d 与 mRNA E2F1 呈正相关。
结论
本研究鉴定了与 I 期 HCC 进展和预后相关的新型 lncRNA 和 mRNA，并进一步研究了 lncRNA 介导的 ceRNA 在 I 期 HCC 发展中的调控机制。
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