miR-181d调控Jak/STAT3信号通路逆转间质型胶质母细胞瘤表型转化的机制研究

Glioblastoma (GBM) is the most common and maligant brain tumor in adults, and survival time of patients varies considerably betweet genetic subtypes. The recent studies relealved the plasticity between GBM molecular subtypes, and in a specific signal pathway dependent fashion. Our preliminary miRNA-mRNA profiling analysis found that the expression of miR-181d significant differences in mesenchymal subtype (MES, poor prognosis) and proneural subtype (PN, better prognosis) in GBM; and the genes associated with biological function of miR-181d were enriched in the Jak/STAT3 pathway. Based on our previous study and the recent research progress, we propose a hypothesis that targeting miR-181d may promote the transformation of MES forward PN phenotype through regulating STAT3 signaling, thus improving the malignant biological behavior of tumors. To verify the hypothesis, we intend to analyze the mechanistic link bewtween miR-181d and Jak/STAT3 pathway, which play an integral role in GBM subtype transformation, through the experiments in vitro and in vivo. And further clarify the feasibility that miR-181d reverses MES malignant phenotype. The present study will avenue to new ideas for using of miRNA in malignant tumor.

胶质母细胞瘤（GBM）是最常见和恶性呈度最高的脑肿瘤，不同分子亚型间生存预后存在较大差异。最近研究发现GBM分子亚型之间可以发生转化，且以特定信号通路依赖的方式进行。我们前期在miRNA-mRNA表达谱跨平台分析发现，miR-181d在间质型(MES，预后极差)和前神经元型（PN，预后较好）GBM中呈显著差异性表达；与miR-181d生物学相关的基因富集于Jak-STAT3信号通路。基于前期工作基础并结合国际最近研究进展，我们提出假说：通过miR-181d–Jak/STAT3调控网络促进MES型GBM向PN型表型转化，从而改善肿瘤的生物学行为。本项目将通过体、内外实验技术，深入解析miR-181d与GBM亚型转化核心通路Jak/STAT3的关系，阐明通过干预miR-181d调控GBM亚型转化的可行性，最终为miRNA运用于恶性肿瘤的治疗提供思路和理论支持。

胶质母细胞瘤（GBM）是最常见和恶性呈度最高的脑肿瘤，不同基因亚型间生存预后存在较大差异。研究发现间质型(MES，预后极差)和前神经元型（PN，预后较好）之间可以发生转化，NFκB信号网络在胶质瘤间质表型转化中发挥了关键作用。我们通过miRNA-mRNA表达谱跨平台分析中发现，miR-181d在MES和PN型GBM中呈显著差异性表达。本项目旨在探索miR-181d在GBM表型转化中的作用及其机制，通过解析miR-181d与胶质瘤表型转化相关信号通路NFkB的关系，来为干预miR-181d来调控胶质瘤亚型转化提供理论支持。..在本研究中，我们基于GBM基因组数据库的生物信息挖掘发现，miR-181d功能与STAT3-NFκB信号通路相关基因密切相关。进一步生物信息分析和荧光素酶报告实验证实，miR-181d能够通过直接靶向NFκB通路的关键信号蛋白MALT1。在体和体外实验均表明miR-181d过表达可以通过靶向MALT1下调NFκB通路的转录活性，进而引起胶质瘤亚型标志性基因表达改变(MES：CD44、Vim表达下降；PN：PDGFRa、Olig2表达升高），抑制胶质瘤恶性生物学行为，增加胶质瘤细胞对X线放疗及替莫唑胺化疗的敏感性。本研究本着转化医学的理念，阐明通过干预miR-181d调控GBM亚型转化的分子机制，为miRNA运用于恶性胶质瘤的分子靶向治疗提供了理论可行性。