基于多层次调控与代谢整合网络的肝癌分子分型及潜在治疗靶点预测研究

发掘精准的分子分型方案和治疗靶点是肿瘤精准医学领域有待突破的瓶颈，发展多层次网络整合的生物信息学方法解析调控与代谢影响肿瘤细胞生长的机制有助于分型和潜在靶点发现。本项目拟通过建立整合转录调控、表观调控与代谢多层次网络的新方法，开展肝癌相关miRNA-转录因子-基因-蛋白/酶-代谢物的多层次关联研究。在前期基础上，利用TCGA肝癌样本表达谱数据，采用多种调控推断算法和多重证据构建miRNA、转录因子、基因之间的调控作用网络，再与肝组织代谢网络模型整合，并以代谢通量平衡模拟为核心，发掘影响肝癌细胞生长的关键调控因子、代谢基因和通路。基于建立的多层次整合网络对肝癌样本进行分型，预测新的预后标志物，发现显著抑制肝癌细胞生长的基因作为潜在治疗靶点，对2-3个靶基因进行细胞水平功能验证。本项目将为多组学多层次的整合生物网络构建提供方案，为揭示肝癌调控-代谢交互机制、推动肝癌及其他肿瘤精准诊疗提供参考。

The discovery of precise molecular subtyping and therapeutic targets are the bottlenecks in the field of cancer precision medicine. Developing new bioinformatics methods on multi-level network integration to uncover mechanisms of regulation and metabolism affecting cancer cell growth is helpful for subtyping and potential targets identification. This project intends to establish a new method to integrate multi-level networks of transcriptional regulation, epigenetic regulation and metabolism, analyze the comprehensive association of miRNA-TF-gene-protein/enzyme-metabolite in Hepatocellular Carcinoma. Based on previous study, by using the mRNA and miRNA expression profile data of TCGA LIHC samples, different regulatory inference algorithms and multiple evidences will be taken to construct a regulatory network between miRNA, TF, and gene, and then integrated with the liver tissue specific metabolic network model. Comprehensive analysis based on flux balance simulation were used to discover key regulatory factors, metabolic genes and pathways that affect the growth of cancer cells. Based on the multi-level integrated network, we will stratify the HCC samples, identify prognostic markers, and predict genes that significantly inhibit tumor cell growth as potential therapeutic targets. We will further validate 2-3 key candidates by cell line experiments. This project will provide efficient solution for multi-omics/multi-level integrated network study, and provide guideline for revealing the crosstalking mechanisms between regulation and metabolism and promoting the precise diagnosis/treatment of Hepatocellular Carcinoma and other tumors.