SREBP1介导的SCD1表达在调控脂质代谢及维持胶质瘤干细胞干性的作用及机制研究

It has become a hot topic in the world to find the metabolic markers which can maintain the function of cancer stem cells and to interfere with the metabolic mechanism to inhibit tumor growth. Sterol regulatory element-binding protein 1 (SREBP1) and Stearoyl-Coenzyme A desaturase 1 (SCD1) play an important role in the in the regulation of monounsaturated fatty acids (MUFA) metabolism, but its mechanism on cancer metabolism is still unclear. The preliminary results of this project showed that SREBP1 is highly expressed in glioma stem cells (GSCs), inhibition of SREBP1 can effectively reduced the level of MUFA in GSCs and effectively eliminated GSCs, and SCD1 is the rate-limiting enzyme of in the MUFA synthesis. Accordingly, we hypothesize that SREBP1 can regulates MUFA metabolism by regulating SCD1 transcriptional activity, and MUFA plays an important role on maintaining the properties of GSCs. In this project, on the basis of research results in the earlier stage, using genetic intervention and pharmacological methods, to explore the regulatory mechanism between SREBP1 and SCD1 in the regulation of MUFA, and investigate the effect and mechanism of MUFA metabolism on maintaining the properties of GSCs. The objective of this work not only provides a new theory for the key molecular mechanism of GSCs lipid metabolism, but also opens up a new way for cancer detection and targeted therapy.

寻找维持肿瘤干细胞功能至关重要的代谢标志并干预这种代谢机制以抑制肿瘤生长已成为国内外研究热点。固醇调节元件结合蛋白1（SREBP1）与硬脂酰辅酶A去饱和酶1（SCD1）在调控单不饱和脂肪酸（MUFA）代谢中发挥重要作用，但其与肿瘤代谢机制仍不清楚。本项目前期研究结果发现：胶质瘤干细胞（GSCs）中SREBP1呈高表达，抑制SREBP1后可有效降低GSCs内MUFA水平并抑制其干性，而SCD1是合成MUFA的限速酶。据此我们提出科学假说：SREBP1经SCD1调控MUFA代谢在GSCs干性维持中具有重要作用。本项目拟运用基因干预和药理学等方法，从分子、细胞和个体水平阐明SREBP1和SCD1之间的调控机制，并探讨其影响MUFA代谢在GSCs干性维持中的作用及机制。本项目的实施不仅为GSCs脂质代谢的关键分子机理提供新理论，而且为肿瘤的检测和靶向治疗开辟了一条新的途径。

寻找维持肿瘤干细胞功能至关重要的代谢标志并干预这种代谢机制以抑制肿瘤生长已成为国内外研究热点。固醇调节元件结合蛋白1（SREBP1）与硬脂酰辅酶A去饱和酶1（SCD1）在调控单不饱和脂肪酸（MUFA）代谢中发挥重要作用，但其与肿瘤代谢机制仍不清楚。本项目前期研究结果发现：胶质瘤干细胞（GSCs）中SREBP1呈高表达，抑制SREBP1后可有效降低GSCs内MUFA水平并抑制其干性，而SCD1是合成MUFA的限速酶。据此我们提出科学假说：（1）SREBP1经SCD1调控MUFA代谢在GSCs干性维持中具有重要作用；（2）RET通过HBP调控SCAP蛋白N-糖基化可能是SREBPs水解激活以促进脂代谢的关键机制。本项目拟运用基因干预和药理学等方法，从分子、细胞和个体水平阐明SREBP1和SCD1之间的调控机制，并探讨其影响MUFA代谢在GSCs干性维持中的作用及机制。结果显示：(1)药理学抑制SREBP-1可抑制脂质代谢并促进胶质瘤干细胞凋亡（2）SREBP1在胶质瘤及其干细胞中高表达且与患者的预后呈负相关性（3）RET信号通路经HBP调控SCAP N-糖基化进而促进脂质代谢（4）SCAP N-糖基化位点位于N263、N590、N641位（5）抑制SCAP蛋白N-糖基化可有效杀伤GSCs。证实了SREBP1/SCD1调控不饱和脂肪酸代谢是维持胶质瘤干细胞功能至关重要的代谢途径，为难治性胶质瘤的生物学治疗开拓了新思路，进一步揭示了RET信号通路可通过增强HBP代谢进而促进SCAP N-糖基化，进而促进SREBP-1水解激活以促进脂质代谢，明确癌信号RET与脂质代谢失调之间的复杂相互作用。

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