环状RNA circRIMS2调控胶质瘤干细胞增殖、分化和耐药的功能及机制

Glioma stem cells (GSCs) are the source of gliomagenesis, development, treatment resistance and tumor recurrence.The elimination of GSCs in the tumor,therefore, has been regarded as the fundamental strategy to cure the disease. However, the molecular mechanisms underlying GSCs maintenance and differentiation remain unknown. Our preliminary study showed that circular RNA(circRNA) expression profiles were significantly altered during the differentiation of GSCs. Amongst, circRIMS2 was found to be able to directly interact with the key miRNA regulators of cancer stem cell maintenance, e.g. miR-124, and regulated the expression of corresponding miRNAs as well as GSCs viability. Therefore, we hypothesize that circRIMS2 plays important roles in the self-renewal and differentiation of GSCs through interacting with specific miRNAs. In present study, we aim to investigate further the functions and mechanisms of circRIMS2 in regulating GSCs maintenance, differentiation and treatment resistance by employing both in vitro and in vivo GSCs models. We will study the effect of circRIMS2 expression alteration on the self-renewal, differentiation and apoptosis of GSCs in vitro, as well as their tumorigenic ability and chemo-sensitivity changes in vivo. We will also explore the correlation between the blood level of circRIMS2 and glioma patient prognosis. Our study will provide novel insights into the functional mechanismsof GSCs proliferation, differentiation and chemo-resistance, and thus potential biomarker for glioma diagnosis and treatment.

胶质瘤干细胞是胶质瘤发生、发展、耐药和复发的根源，但其自我更新和分化的分子机制尚不完全清楚。我们前期研究发现，胶质瘤干细胞分化过程中，一批环状RNA（circular RNA,circRNA）的表达发生显著变化，其中circRIMS2能直接与肿瘤干细胞分化的关键调控因子miR-124等互作，并调控着miR-124的表达和胶质瘤干细胞的活性。由此我们推测，circRIMS2在胶质瘤中通过与miRNA互作，对胶质瘤干细胞的增殖和分化发挥着关键调控作用。在此基础上，本项目拟通过干预circRIMS2表达，在体外细胞和体内小鼠模型中探索其与miRNA互作调控胶质瘤干细胞增殖、分化、成瘤及耐药的作用及机制，并在临床血液标本中分析circRIMS2表达水平与胶质瘤病人预后生存的关系，探索circRIMS2的临床应用价值。本研究将为胶质瘤的诊断、治疗和预后分析提供有潜在应用价值的新靶点。

胶质瘤干细胞是胶质瘤发生、发展、耐药和复发的根源。非编码RNA(ncRNA)参与胶质瘤干细胞的自我更新和分化,但其分子机制仍有待阐明。本项目系统研究非编码RNA，尤其是环状RNA（circRNA）在胶质瘤肿瘤发生和发展中的功能和机制。我们首先探讨了RNA结合蛋白(RBP)与ncRNA互作，在癌症发生中的潜在功能。我们整合了癌症高通量CLIP-Seq测序数据系统发掘ncRNA与RBP的互作网络。我们鉴定出了76个可潜在引发癌症的driver RBP，还发现了139个在癌症中明显突变的RBP。该部分研究发表在Cell reports上。此外，我们还从表观遗传调控方面探讨ncRNA表达和功能异常在肿瘤发生中的作用。我们开发了计算机软件包modAnnotator和metaProfile从高通量测序数据中识别表观遗传调控的RNA修饰位点，比如m6A修饰，2’-O-methylation（2-氧-甲基化修饰）等，我们分析了这些表观遗传调控与ncRNA表达异常的关系，及与肿瘤发生发展的关系。我们还探讨了表观遗传修饰位点与疾病相关的单核苷酸多态性(SNP)之间的关系。该部分研究发表在 Methods in Molecular Biology (Springer series)上。另外，我们还建立了ncRNA互作分析平台（deepBase v3.0）,从高通量测序数据中挖掘分析不同种类ncRNA之间（比如miRNA与lncRNA、circRNA与miRNA和circRNA与lncRNA）的互作关系，及它们在肿瘤发生中的潜在功能。该部分研究发表在Nucleic Acids Research上。这些工作为我们系统了解包括circRNA在内的ncRNA在肿瘤中的功能和机制提供了重要信息和依据。