LMAR/SREBP1a调控肝内胆管癌脂代谢重编程的机制研究

Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy associated with unfavorable prognosis and for which no effective treatments are available. Our previous research results have shown that lncRNA and its target genes play an important role in tumor metabolism, in which lncRNA-LMAR can bind to the steroid regulatory element binding protein (SREBP1a) to participate in the lipid metabolism of cholangiocarcinoma cells. The expression of LMAR and SREBP1a in ICC cell lines and cancer tissues were significantly up-regulated, suggesting that LMAR/SREBP1a could act as a complex through interact with other factors and regulate the expression and function of downstream target genes to influence ICC's lipid metabolism reprogramming. However, its mechanism and related factor, signaling pathway are still unknown. This study will focus on: 1) the biological functions of LMAR and SREBP1a and their effects on lipid metabolism; 2) the interaction between LMAR/ SREBP1a complex and related protein factors; 3) the downstream target genes and signaling pathway of LMAR/SREBP1a in lipid metabolism reprogramming. This study will explore the role of lipid metabolism reprogramming in the development and progression of ICC from the new perspective of lncRNA scaffold function and protein factor interaction and its effect on lipid metabolism, and provide a solid foundation for ICC treatment.

肝内胆管癌(ICC)恶性度高、预后差、缺乏有效治疗手段。我们前期研究发现，lncRNA及其靶基因在肿瘤代谢中发挥着重要作用，其中lncRNA-LMAR能够与固醇调节元件结合蛋白-1a(SREBP1a)相互结合，共同参与脂质代谢。LMAR与SREBP1a在ICC细胞系和癌组织中表达显著上调，提示两者可能以复合体的模式作用于下游靶基因的表达及功能，进而调控ICC的脂代谢重编程，但其作用机制未明。本项目将研究：1)LMAR和SREBP1a的生物学功能及其对脂代谢的影响; 2)两者相互调控机制及参与其中的蛋白因子; 3)两者共同调控的下游靶基因及信号通路在ICC脂代谢重编程中的作用和机制。本课题将从lncRNA分子支架功能和蛋白因子相互作用及其对脂代谢影响的新视点，阐明LMAR/SREBP1a调控脂代谢的机制，为从脂代谢角度诊治ICC提供新的思路。

肝内胆管癌（intrahepatic cholangiocarcinoma， ICC）是肝脏第二大原发性恶性肿瘤，由于其发病隐匿、转移早，仅有10%～15%患者能得到根治性切除。肿瘤代谢重编程是肿瘤发生发展过程中的重要特征之一。越来越多研究证实lncRNA可以通过影响代谢重编程影响肿瘤进展。由于ICC存在于脂代谢旺盛的肝脏微环境中，我们推测ICC存在脂代谢重编程，拟探究lncRNA通过影响脂代谢重编程介导ICC细胞侵袭转移的机制。以期找到ICC的特异性生物标志物，并为ICC肿瘤治疗找到突破口。.本课题主要研究LMAR(TUG1)在ICC肿瘤和癌旁组织中的表达及临床意义，同时研究LMAR(TUG1)对脂代谢重编程的影响，进而探究LMAR(TUG1)通过促进脂代谢重编程影响ICC侵袭转移的机制。.研究发现LMAR(TUG1)在肝内胆管癌组织中高表达，且高表达LMAR(TUG1)提示患者预后差。进一步细胞实验发现，在敲减LMAR(TUG1)时，细胞侵袭转移能力下降，细胞内游离脂肪酸和中性脂滴含量下降。机制研究我们发现LMAR(TUG1)是通过LMAR(TUG1)/miR-144-3p/FABP5轴影响ICC细胞的侵袭转移的，此外LMAR(TUG1)也可与SREBP1a相互结合可能影响ICC细胞侵袭转移。.研究ICC的侵袭转移机制是一项复杂而有意义的工作。从代谢重编程角度探究ICC侵袭转移机制可能是未来研究的方向之一，我们的研究成果为后续从脂代谢重编程角度研究ICC侵袭转移提供一定的指导。