NIR调控核糖体DNA转录和蛋白质合成促胶质瘤干细胞增殖与自我更新的机制研究

肿瘤细胞会经历一系列复杂的代谢重编程来维持自身的快速增殖，其中蛋白质合成的增加对肿瘤的发生和发展至关重要。然而，在胶质母细胞瘤特别是胶质瘤干细胞中，控制核糖体生物发生和蛋白质合成的分子机制至今仍不清楚。我们初步的研究结果显示，转录因子NIR主要由胶质瘤干细胞表达，并且促进了胶质瘤干细胞的体外生长以及胶质母细胞瘤的颅内生长。我们发现NIR主要定位于胶质瘤干细胞的核仁内，并且敲降NIR可以显著抑制核糖体DNA转录和蛋白质合成。通过免疫共沉淀和液相色谱-质谱联用分析，我们发现参与核糖体DNA转录的转录因子NCL和NPM1与NIR相结合。因此在本项目中，我们将进一步研究NIR在细胞和动物水平上对胶质瘤干细胞增殖、自我更新及其它相关功能的影响，并阐明NIR调控核糖体DNA转录和蛋白质合成的分子机制。本项目的研究将有助于从代谢角度理解胶质瘤干细胞恶性增殖和自我更新的分子基础并提供新的治疗靶点。

Cancer cells undergo complex metabolic reprogramming to support the rapid proliferation. Among them, the increased protein synthesis is essential for tumorigenesis and progression. However, the molecular mechanisms that govern ribosome biogenesis and protein synthesis in glioblastoma (GBM), especially in glioblastoma stem cells (GSCs), are still unclear. Our preliminary results showed that NIR was preferentially expressed by GSCs, and NIR promoted GSC growth in vitro and GBM growth in vivo. We found that NIR was localized in the nucleoli of GSCs, and silencing NIR markedly inhibited ribosomal DNA transcription and protein synthesis. We further found that NCL and NPM1, two important transcription factor involved in ribosomal DNA transcription, bound to NIR through CoIP-LC/MS analysis. In this proposal, we will further investigate the role of NIR on GSC proliferation、self-renewal and other functions in vitro and in vivo, and clarify the molecular mechanism of NIR in promoting ribosomal DNA transcription and protein synthesis. Our project will help to understand the molecular basis of the malignant proliferation and self-renewal of GSCs in the perspective of cell metabolism and provide a new potential therapeutic target.