ATF4调控的lncRNA GILR1经由SYK/mTOR通路在肾癌细胞谷氨酰胺饥饿应激中的作用及机制研究

葡萄糖和谷氨酰胺是肿瘤细胞依赖但又缺乏的营养来源，肿瘤细胞需要调控基因表达适应营养缺乏来不断增殖。我们及他人的研究表明lncRNA在肿瘤葡萄糖饥饿应激中发挥重要作用，然lncRNA在肿瘤谷氨酰胺饥饿应激中的功能尚待阐明。通过RNA-seq，我们在786-O肾透明细胞癌细胞中发现上百个全新的谷氨酰胺饥饿应激lncRNA。其中，GILR1作为受ATF4调控的lncRNA分子，能与SYK蛋白结合并增加其稳定性，能上调mTOR通路活性。SYK是mTOR通路已知的调控因子，据此我们提出假说：受ATF4调控的GILR1结合并增加SYK蛋白稳定性，进而增强mTOR通路活性，最终调节细胞谷氨酰胺饥饿适应性。本课题拟采用分子与细胞生物学方法，利用细胞实验、裸鼠荷瘤模型及肿瘤组织样本，研究GILR1的功能和作用机制。本研究将能加深lncRNA在肿瘤谷氨酰胺代谢调控中的科学认识，并为肾癌的诊治提供新的潜在靶点。

Glucose and glutamine are two major but normally deficient nutritional sources for tumor cells. In order to proliferate continually, tumor cells need regulate genes expression to accommodate the lack of glucose and glutamine. Our and others' studies have shown that lncRNA plays an important role in the adaption to glucose starvation stress in tumor cells. However, the function of lncRNA in the adaption to glutamine starvation stress in tumor cells is poorly understood. We identified more than one hundred novel glutamine starvation stress response lncRNA genes in renal clear cell carcinoma 786-O cells by RNA-seq. We found GILR1 as a ATF4-regulated lncRNA, which can bind to SYK protein and increase its stability. In addition, GILR1 can up-regulate the activity of mTOR signaling. Previous studies have identified SYK as an important regulator of mTOR signaling. Accordingly, we hypothesize that ATF4-regulated GILR1 binds to and stabilizes SYK proteins, enhances mTOR activity and ultimately regulates the adaptation of cells to glutamine starvation stress. In this proposal, we are going to use molecular and cellular methods to study the function and mechanism of GILR1 in cell models, nude mice tumor models and tumor tissue samples. Our proposed study will have significant impact on understanding the gene regulation mediated by lncRNA in the adaptation to glutamine starvation stress in tumor cells and provide new potential targets for renal cell carcinoma diagnosis and treatment.