长链非编码RNA相关的竞争性内源RNA网络分析揭示了人类结肠腺癌中潜在的长链非编码RNA生物标志物。
Analysis of lncRNA-Associated ceRNA Network Reveals Potential lncRNA Biomarkers in Human Colon Adenocarcinoma.
作者信息
Zhang Zhiyuan, Qian Wenwei, Wang Sen, Ji Dongjian, Wang Qingyuan, Li Jie, Peng Wen, Gu Jiou, Hu Tao, Ji Bing, Zhang Yue, Wang Shijia, Sun Yueming
机构信息
The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
出版信息
Cell Physiol Biochem. 2018;49(5):1778-1791. doi: 10.1159/000493623. Epub 2018 Sep 19.
BACKGROUND/AIMS: Long non-coding RNAs (lncRNAs) acting as competing endogenous RNAs (ceRNAs) play significant roles in the development of tumors, but the functions of specific lncRNAs and lncRNA-related ceRNA networks have not been fully elucidated for colon adenocarcinoma (COAD). In this study, we aimed to clarify the lncRNA-microRNA (miRNA)-mRNA ceRNA network and potential lncRNA biomarkers in COAD.
METHODS
We extracted data from The Cancer Genome Atlas (TCGA) and identified COAD-specific mRNAs, miRNAs, and lncRNAs. The biological processes in Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were analyzed for COAD-specific mRNAs. We then constructed a ceRNA network of COAD-specific mRNAs, miRNAs and lncRNAs and analyzed the correlation between expression patterns and clinical features of the lncRNAs involved. After identifying potential mRNA targets of 4 lncRNAs related to overall survival (OS), we conducted stepwise analysis of these targets through GO and KEGG. Using tissue samples from our own patients, we also verified certain analytical results using quantitative real-time PCR (qRT-PCR).
RESULTS
Data from 521 samples (480 tumor tissue and 41 adjacent non-tumor tissue samples) were extracted from TCGA. A total of 258 specific lncRNAs, 206 specific miRNAs, and 1467 specific mRNAs were identified (absolute log2 [fold change] > 2, false discovery rate < 0.01). Analysis of KEGG revealed that specific mRNAs were enriched in cancer-related pathways. The ceRNA network was constructed with 64 lncRNAs, 18 miRNAs, and 42 mRNAs. Among these lncRNAs involved in the network, 3 lncRNAs (LINC00355, HULC, and IGF2-AS) were confirmed to be associated with certain clinical features and 4 lncRNAs (HOTAIR, LINC00355, KCNQ1OT1, and TSSC1-IT1) were found to be negatively linked to OS (log-rank p < 0.05). KEGG showed that the potential mRNA targets of these 4 lncRNAs may be concentrated in the MAPK pathway. Certain results were validated by qRT-PCR.
CONCLUSION
This study providing novel insights into the lncRNA-miRNA-mRNA ceRNA network and reveals potential lncRNA biomarkers in COAD.
背景/目的：长链非编码RNA（lncRNA）作为竞争性内源性RNA（ceRNA）在肿瘤发生发展中发挥重要作用，但在结肠腺癌（COAD）中，特定lncRNA的功能及lncRNA相关的ceRNA网络尚未完全阐明。本研究旨在明确COAD中的lncRNA-微小RNA（miRNA）-信使核糖核酸（mRNA）ceRNA网络及潜在的lncRNA生物标志物。
方法
我们从癌症基因组图谱（TCGA）中提取数据，鉴定出COAD特异性的mRNA、miRNA和lncRNA。对COAD特异性mRNA进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）中的生物学过程分析。随后构建COAD特异性mRNA、miRNA和lncRNA的ceRNA网络，并分析所涉及lncRNA的表达模式与临床特征之间的相关性。在确定4个与总生存期（OS）相关的lncRNA的潜在mRNA靶点后，我们通过GO和KEGG对这些靶点进行逐步分析。利用我们自己患者的组织样本，我们还通过定量实时聚合酶链反应（qRT-PCR）验证了某些分析结果。
结果
从TCGA中提取了521个样本（480个肿瘤组织和41个相邻非肿瘤组织样本）的数据。共鉴定出258个特异性lncRNA、206个特异性miRNA和1467个特异性mRNA（绝对log2[倍数变化]>2，错误发现率<0.01）。KEGG分析显示，特异性mRNA在癌症相关通路中富集。构建了由64个lncRNA、18个miRNA和42个mRNA组成的ceRNA网络。在该网络中涉及的这些lncRNA中，3个lncRNA（LINC00355、HULC和IGF2-AS）被证实与某些临床特征相关，4个lncRNA（HOTAIR、LINC00355、KCNQ1OT1和TSSC1-IT1）被发现与OS呈负相关（对数秩检验p<0.05）。KEGG显示，这4个lncRNA的潜在mRNA靶点可能集中在丝裂原活化蛋白激酶（MAPK）通路。某些结果通过qRT-PCR得到验证。
结论
本研究为lncRNA-miRNA-mRNA ceRNA网络提供了新的见解，并揭示了COAD中潜在的lncRNA生物标志物。
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