病毒性肝炎恶性转化的多元调控网络研究

Inflammatory responses and microenvironment induced by persistent viral hepatitis play important roles at different stages of hepatocellular carcinoma (HCC) development, including initiation, promotion, invasion, and metastasis. However, the molecular pathogenesis of this process is not fully understood. Thus, it is necessary to explore the regulatory network between inflammatory cells and hepatocytes/HCC cells. In this study, we will take advantage of small RNA and polyA +/- RNA sequencing technologies, microarray analysis, bioinformatics, systems biology, and molecular biology in the clinical samples representative of different stages of malignant transformation. Through real-time monitoring the dynamic changes of various molecules in lymphocytes, macrophages and hepatocytes/HCC cells during this process, we will construct a multivariant regulatory network for each type of cells. After analyzing the topological properties and functional modules, we aim to find the key modules and molecules among the three networks by using a network-comparing algorithm, and validate their significance in future clinical diagnosis and treatment by conducting experimental intervention treatment on animal models.

病毒性肝炎所致的炎性反应及炎性环境对肝细胞癌的发生、发展有着重要的作用。然而，目前对于病毒性肝炎诱导肝细胞癌变的机制尚不清楚。因此，研究炎性细胞与肝/肝癌细胞间的调控网络对于揭示慢性炎症向肝细胞癌转化的机制有着重要的意义。本研究应用病毒性肝炎引发肝细胞癌过程中各阶段临床样本，综合运用小RNA、mRNA及长非编码RNA高通量测序技术、芯片检测、生物信息学分析、系统生物学及分子生物学等手段，通过实时监测炎症恶性转化过程各阶段淋巴细胞、巨噬细胞及肝/肝癌细胞中各类分子的动态变化，分别构建含有小RNA、mRNA、长非编码RNA及多种调控模式的多元调控网络。通过对三类多元调控网络中拓扑结构、功能模块分析，利用网络模块比对算法，找到炎症恶性转化过程中淋巴细胞、巨噬细胞与肝细胞癌变之间起关键作用的功能模块，找出其中关键因子，并针对关键节点进行动物水平的实验干预性治疗以证实其在未来临床诊断及治疗上的意义。

病毒性肝炎所致的炎性反应及炎性环境对肝细胞癌的发生、发展有着重要的作用。然而，目前对于病毒性肝炎诱导肝细胞癌变的机制尚不清楚。本课题对病毒性肝炎引发的肝细胞癌的分子机制及调控网络进行了系统的分析，我们采用全基因组测序、全转录组测序，以及蛋白组学测序等多种手段，对肝癌调控网络中的核心基因进行了深入研究。同时，我们开发和优化了长非编码RNA鉴定算法及数据库，对调控网络中的长非编码基因进行了系统的分析。本课题的研究结果不仅为广大的基础研究人员提供了丰富的参考信息，同时为临床应用提供了诊断标记及药物靶点等重要信息。