Gao Bo, Zhang Xueming, Huang Yongming, Yang Zhengpeng, Zhang Yuguo, Zhang Weihui, Gao Zu-Hua, Xue Dongbo
Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Department of Pathology, The Research Institute of McGill University Health Centre, Montreal, Quebec, Canada.
PLoS One. 2017 Mar 29;12(3):e0174142. doi: 10.1371/journal.pone.0174142. eCollection 2017.
Liver cirrhosis is recognized as being the consequence of immune-mediated hepatocyte damage and repair processes. However, the regulation of these immune responses underlying liver cirrhosis has not been elucidated. In this study, we used GEO datasets and bioinformatics methods to established coding and non-coding gene regulatory networks including transcription factor-/lncRNA-microRNA-mRNA, and competing endogenous RNA interaction networks. Our results identified 2224 mRNAs, 70 lncRNAs and 46 microRNAs were differentially expressed in liver cirrhosis. The transcription factor -/lncRNA- microRNA-mRNA network we uncovered that results in immune-mediated liver cirrhosis is comprised of 5 core microRNAs (e.g., miR-203; miR-219-5p), 3 transcription factors (i.e., FOXP3, ETS1 and FOS) and 7 lncRNAs (e.g., ENTS00000671336, ENST00000575137). The competing endogenous RNA interaction network we identified includes a complex immune response regulatory subnetwork that controls the entire liver cirrhosis network. Additionally, we found 10 overlapping GO terms shared by both liver cirrhosis and hepatocellular carcinoma including "immune response" as well. Interestingly, the overlapping differentially expressed genes in liver cirrhosis and hepatocellular carcinoma were enriched in immune response-related functional terms. In summary, a complex gene regulatory network underlying immune response processes may play an important role in the development and progression of liver cirrhosis, and its development into hepatocellular carcinoma.
肝硬化被认为是免疫介导的肝细胞损伤和修复过程的结果。然而，肝硬化背后这些免疫反应的调节机制尚未阐明。在本研究中，我们使用基因表达综合数据库（GEO）数据集和生物信息学方法建立了编码和非编码基因调控网络，包括转录因子-/长链非编码RNA-微小RNA-信使RNA以及竞争性内源RNA相互作用网络。我们的结果确定了2224个信使RNA、70个长链非编码RNA和46个微小RNA在肝硬化中差异表达。我们发现导致免疫介导的肝硬化的转录因子-/长链非编码RNA-微小RNA-信使RNA网络由5个核心微小RNA（如miR-203；miR-219-5p）、3个转录因子（即叉头框蛋白P3、ETS1和FOS）和7个长链非编码RNA（如ENTSO00000671336、ENST00000575137）组成。我们确定的竞争性内源RNA相互作用网络包括一个控制整个肝硬化网络的复杂免疫反应调节子网络。此外，我们发现肝硬化和肝细胞癌共有的10个重叠基因本体（GO）术语中也包括“免疫反应”。有趣的是，肝硬化和肝细胞癌中重叠的差异表达基因在免疫反应相关功能术语中富集。总之，免疫反应过程背后的复杂基因调控网络可能在肝硬化的发生发展及其向肝细胞癌的转变中发挥重要作用。
