RNA编辑型IGFBP7在肿瘤细胞与肿瘤血管微环境中的调控作用及机制研究

前期研究首次发现A到I的RNA编辑是癌细胞中蛋白质组多样性的来源之一，挖掘并鉴定了非同义突变RNA编辑位点IGFBP7_R78G。ADAR2在多种类型肿瘤中调控IGFBP7的RNA编辑，其RNA编辑水平与多种肿瘤的临床资料指标相关。RNA编辑型IGFBP7不仅促进癌细胞的增殖与迁徙，还促进血管内皮细胞的成管、伸展和迁徙。本项目拟在前期工作基础上，首先通过RNA测序、SILAC、血管生成因子抗体芯片和非靶向代谢组学的联合多组学分析以及聚焦检测各个“明星”靶标，系统深入解析RNA编辑型IGFBP7在肿瘤细胞和肿瘤血管微环境中调控作用的机制；然后小鼠模型验证及用抑制剂或纳米脂质体治疗荷瘤鼠；最后利用大数据阐释RNA编辑型IGFBP7与泛癌患者临床资料、靶标及药物敏感性的关系。旨在揭示RNA编辑型IGFBP7调控肿瘤发生发展的机理，为肿瘤血管靶向药物研发与癌症个体化精准治疗提供一个新视角。

As an important type of epigenetic regulation mechanism, we have shown that A-to-I RNA editing contributes to proteomic diversity in cancer through changes in amino acid sequences. Our preliminary results have identified adenosine-to-inosine (A to I) RNA editing of IGFBP7 (Insulin Like Growth Factor Binding Protein 7), which is highly correlated with the various cancer. RNA editing of IGFBP7 is regulated by ADAR2 (adenosine deaminase RNA specific B1, ADARB1/ ADAR2) in pan-cancer. Overexpression of the edited IGFBP7 protein not only increases proliferation and migration of lung adenocarcinoma cells, but also promotes tube formation, extension and migration of vascular endothelial cells in vitro. However, the underlying molecular mechanisms remain largely unknown. The current project aims to utilize the RNA sequencing, SILAC (stable isotope labeling with amino acid in cell culture) technology, angiogenesis profiling array and untargeted metabolomics to uncover the critical signaling molecules and pathways that mediate the tumor-prompting activity of RNA-edited IGFBP7. In particular, we will focus on the star targets that are essential to regulate the cell growth and angiogenesis of tumor, respectively. We shall then validate and recapitulate our findings, and also study the effect of RNA-edited IGFBP7 on the role of tumor by using in vivo mouse models. Importantly, through some inhibitors and nanoliposomal delivery, we will evaluate the effect of inhibiting tumor growth and extending survival of mice. Last but not least, big data mining is applied to elucidate the relationship between RNA-edited IGFBP7 and clinical data of patients with pan-cancer, targets and drug sensitivity. The project highlights the translational potential of edited IGFBP7 as a new class of cancer therapeutics，especially for the individualized and precise treatment of cancer. The project will ultimately provide important molecular insights into the tumorigenesis that may pave the way for designing novel drugs targeting tumor vascular with improved efficacy.