RACK1通过GFAT1/O-GlcNAc糖基化轴调控胰腺癌上皮间质转化的功能机制研究

胰腺癌是全球致死率最高的恶性肿瘤之一，上皮间质转化是导致胰腺癌侵袭转移和患者不良预后的重要原因之一。氨基己糖合成途径是葡萄糖代谢的分支，通过控制UDP-GlcNAc产生来影响细胞内O-GlcNAc等糖基化修饰，并在肿瘤发生发展过程中发挥重要调控作用。RACK1是一个经典构架蛋白，我们前期研究发现RACK1可以通过影响信号传导、表观遗传、蛋白翻译等方面调节肿瘤生长、转移和耐药等过程。然而，RACK1是否能够调控蛋白质糖基化修饰尚不清楚。在本项目中，我们将研究RACK1影响氨基己糖合成途径限速酶GFAT1表达和蛋白质O-GlcNAc糖基化修饰的功能，并探讨GFAT1/O-GlcNAc糖基化轴在RACK1调控胰腺癌上皮间质转化和侵袭转移中的生物学效应和分子机制，从而为阐述氨基己糖合成途径在胰腺癌中的活性调节及其在肿瘤发生发展中的作用提供依据，并为胰腺癌的临床治疗提供新的线索和潜在方案。

Pancreatic cancer is one of the most lethal of all types of cancer worldwide. Epithelial-mesenchymal transition is critical for the invasion and metastasis of pancreatic cancer, and also contributes to the poor prognosis of patients. Hexosamine biosynthetic pathway (HBP) is a branch of glucose metabolism, and modulates protein glycosylation including O-GlcNAcylation via controlling the production of UDP-GlcNAc. Hence, HBP plays a key role in the tumorigenesis and development of tumors. RACK1 is a classical scaffold protein, and our previous studies have indicated the critical role of RACK1 in regulating tumor growth, metastasis and chemoresistance via the modulation of epigenetics, signaling transduction and protein synthesis. However, whether RACK1 could regulate protein glycosylation remains unknown. In this study, we plan to determine the effects of RACK1 on HBP rate-limiting enzyme GFAT1 and protein O-GlcNAcylation pattern. Besides, we will explore the role of GFAT1/O-GlcNAcylation axis in RACK1-mediated regulation of epithelial-mesenchymal transition as well as the invasion and metastasis of pancreatic cancer cells. Thus, our study may uncover novel mechanisms underlying the regulation of hexosamine biosynthetic pathway activation and its role in regulating tumorigenesis and development of pancreatic cancer, and provide new strategies for the clinical treatment of pancreatic cancer.