HBV^+肝细胞癌患者lncRNA-mRNA共表达网络分析及作用

Profiles and functions of lncRNA-mRNA co-expression network in HBV^+ hepatocellular carcinoma patients

目的分析乙型肝炎病毒阳性(HBV+)肝细胞癌患者肝组织长链非编码RNA(long noncoding RNA,lncRNA)和信使RNA(messenger,mRNA)的共表达网络,探讨关键lncRNA的作用。方法下载GEO(GSE54238)lncRNA/mRNA表达谱芯片数据,通过生物信息数据分析方法获得不同临床进展阶段的肝细胞癌患者与正常人均具有显著差异的肝组织lncRNA、mRNA表达谱,并构建被DNA元素百科全书数据库(Encyclopedia of DNA Elements,ENCODE)收录的差异lncRNA-mRNA共表达网络。继而分析共表达网络中的mRNA参与的GO、KEGG;并分析与核心lncRNA高度相关的mRNA与患者生存曲线的相关性。结果与5个ENCODE收录的差异lncRNA具有共表达关系的mRNA共有81个(相关系数≥0.90)。lncRNA-mRNA共表达网络中的mRNA主要参与的GO通路有氧化还原、呼吸电子链传递和脂肪酸代谢过程;KEGG信号通路主要有脂肪酸降解、过氧化物酶体增殖物激活受体和β-丙氨酸代谢。与核心LINC01018(又名SRHC)、EHHADH-AS1和F11-AS1高度相关的mRNA SLC2A2、PCK2、EHHADH、F11、FM04和NR1I3与患者生存曲线具有极显著相关性(P<0.01)。结论 LINC01018、EHHADH-AS1、F11-AS1等lncRNA居于LncRNA-mRNA共表达网络的核心位置,在HBV+肝细胞癌发生、发展中具有关键作用,有望成为HBV+肝细胞癌新的诊断和预后指标。

Objective To analyze the profiles of long non-coding RNA （lncRNA）-messenger RNA （mRNA） co-expression network in the patients with hepatitis B virus positive （HBV＋） hepatocellular carcinoma （HCC）, and explore the potential roles of these key lncRNAs in the development of the disease. Methods In the data of lncRNA and mRNA microarray data in GEO （GSE54238）, we firstly analyzed lncRNA-mRNA co-expression network of differential expressed lncRNAs[annotated by Encyclopedia of DNA Elements （ENCODE）] and mRNAs in the patients of cirrhotic liver, early stage HCC and advanced HCC, respectively.Secondly, we performed Gene Ontology （GO） and the Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis of mRNAs in above lncRNA-mRNA co-expression network.Finally, we did the survival curve correlation analysis of mRNAs that highly correlated with these 3 key lncRNAs by using GEO dataset （GSE14520）. Results There were 81 （｜correlation｜≥0.9）mRNAs that were highly co-expressed with the 5 ENCODE-annotated lncRNAs.The mRNAs in the lncRNA-mRNA co-expression network which participates in the GO pathways mainly included oxidation reduction, carboxylic acid catabolic process, and fatty acid metabolic process, and those involvingin KEGG pathways were fatty acid degradation, PPAR signaling pathway, and β-alanine metabolism.The mRNAs （SLC2A2, PCK2, EHHADH, F11, FM04 and NR1I3） that highly co-expressed with the 3 key lncRNAs[LINC01018 （also SRHC）, EHHADH-AS1 and F11-AS1]were significantly correlated with the survival curve of HBV＋ HCCpatients （P 〈 0.01）. Conclusion The 3 key lncRNAs, LINC01018, EHHADH-AS1 and F11-AS1, may play critical roles in the development and progression of HBV＋ HCC.