谷氨酰胺酶抑制剂与敲除lncRNA NCRNA00219联合抗肿瘤的研究

Inhibitors that target glutamine metabolism provide new directions for tumor therapy, however the potential for inhibitors alone to treat tumors is limited. Therapy in combination with these inhibitors is a tendency. Previous studies reveal that lncRNA NCRNA00219 is down-regulated in a wide range of tumors and associated with poor prognosis of patients. NCRNA00219 knockout leads to the dependence on glutamine metabolism elevation. NCRNA00219 knockout in combination with the glutaminase inhibitor compound 968 suppresses tumor significantly. Therefore, we speculate that NCRNA00219 knockout in combination with compound 968 can treat or even cure tumors effectively. Subsequently, we will explore proteins which interact with NCRNA00219 to elucidate the mechanisms of NCRNA00219 in regulating glutamine metabolism. In addition, we will also demonstrate the anti-tumor efficacy of NCRNA00219 knockout in combination with compound 968 in other types of tumors by the mouse xenograft tumor and tumor metastasis model. Our study not only reveals the role and mechanism of NCRNA00219 in regulating glutamine metabolism but also proposes a new anti-tumor therapy targeting tumor glutamine metabolism, which is important for academic development and clinical application.

靶向谷氨酰胺代谢的抑制剂为肿瘤治疗提供了新方向，然而单独用这些抑制剂治疗肿瘤的潜力有限，研究与这些抑制剂联合应用的疗法是新趋势。我们首次发现lncRNA NCRNA00219的表达在多种肿瘤中下调且与患者的预后相关；NCRNA00219敲除的细胞对谷氨酰胺代谢的依赖性显著增强；敲除NCRNA00219联合谷氨酰胺酶抑制剂compound 968处理显著地抑制肿瘤。据此，首次提出NCRNA00219敲除与compound 968联合处理可有效治疗甚至治愈肿瘤的假说。我们将探索NCRNA00219的结合蛋白以阐明NCRNA00219调控谷氨酰胺代谢的机制；并利用裸鼠移植瘤和肿瘤转移模型在多种肿瘤中验证NCRNA00219敲除与compound 968联合的抗肿瘤疗效。本项目在阐明肿瘤调控谷氨酰胺代谢机制的基础上提出靶向肿瘤谷氨酰胺代谢的抗肿瘤新疗法，具有重要的学术意义和潜在临床应用价值。

本课题研究lncRNA NCRNA00219在调控谷氨酰胺代谢中的作用及其机理，揭示NCRNA00219与EZH2蛋白相互结合并调节其在ME1和ME2启动子区的富集，进而影响该区域的H3K27me3修饰水平和该区域ME1和ME2基因表达，最终调控肿瘤谷氨酰胺代谢。研究工作已完成。在研究NCRNA00219与EZH2蛋白结合并调控谷氨酰胺代谢中的机理过程中，我们发现超过90%的与EZH2蛋白结合的RNA是编码蛋白的mRNA，因此启动了mRNA作为非编码RNA与EZH2蛋白相互结合调控组蛋白修饰及下游基因表达的课题。该课题的创新性较强，论文发表于Frontiers in Oncology杂志。传统观念认为编码蛋白的mRNA是DNA与蛋白质之间的信使，然而我们的研究发现与PRC2复合物结合的一部分mRNA可以像长片段非编码RNA一样从表观遗传层面调控PRC2下游基因的表达。以TMEM117的mRNA为例，我们发现它可以与EZH2蛋白相互结合进而影响TSLP基因启动子区H3K27me3的修饰水平，最终调控TSLP基因的表达。TMEM117的mRNA存在EZH2蛋白的结合位点，该位点突变使得TMEM117的mRNA与EZH2蛋白的结合能力下降。同样的，我们在小鼠中也证实编码蛋白的mRNA可以作为非编码RNA调节PRC2下游基因的表达。本项目的研究促使我们全面认识与理解mRNA的生物学功能，有重要的学术意义。

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