Transgelin2介导KRAS和SREBP1交互调控促进脂代谢重编程在胰腺癌中的作用和机制

Lipd metabolic reprogramming is one of hallmark of cancer. However the roles and the underlying mechanisms of lipd metabolic reprogramming in pancreatic cancer remain elusive. Recently, we have found that the key regulator of lipid metabolism, SREBP1, is a prognostic factor of pancreatic cancer. The Transgelin2/SREBP1 complex specifically drives lipid metabolic reprogramming in pancreatic cancer. And the formation of this complex is under-regualted by KRAS, which is essential drive force of pancreatic cancer. Previous studies have suggested that SREBP1 may regulate KRAS protein through lipid metabolites. Accordingly, we propose the working model: crosstalk between KRAS and SREBP1 via Transgelin2 would promote lipid metabolic reprogramming and tumorgenesis in pancreatic caner. Based on this hypothesis, we will study the mechanisms of KRAS regulating the formation of Transgelin2/SREBP1 complex and subsequently promoting lipid metabolic reprogramming. In the meantime, we will analyze the roles of the Transgelin2/SREBP1 complex in regulating KRAS signaling pathway via lipid metabolites. Finally, the roles of KRAS-ERK1/2-Transgelin2/SREBP1 in pancreatic cancer will be analyzed via xenograft models established by pancreatic cancer cells, in which Transgelin2 gene is edited by CRISPR/Cas9. Through this study, we may understand the molecular mechanisms and the important significance of lipid metabolic reprogramming in pancreatic cancer. It will also provide a rationale for precision medicine in pancreatic cancer.

脂代谢重编程是肿瘤发生发展的标志性事件，其在胰腺癌中的作用及机制尚不清楚。本研究组对脂代谢核心调控因子SREBP1的系列研究，发现SREBP1是胰腺癌预后危险因子，且Transgelin2/SREBP1蛋白复合体可特异性重编程胰腺癌脂代谢，此外该复合体的形成受到胰腺癌核心驱动基因KRAS的调节。结合文献报道SREBP1可能通过脂代谢物直接调节KRAS蛋白，故提出“以Transgelin2为桥梁衔接KRAS和SREBP1交互调控诱发胰腺癌”的假说。本项目拟阐明KRAS调节Transgelin2/SREBP1复合体形成及重编程脂代谢的机制；分析Transgelin2/SREBP1复合体经脂代谢物对KRAS的反馈调节作用；并应用CRISPR/Cas9技术编辑胰腺癌细胞的Transgelin2基因，建立荷瘤动物模型，分析该信号通路对胰腺癌的影响，以期为胰腺癌精准医学提供依据。

脂代谢重编程是肿瘤发生发展的标志性事件，其在胰腺癌中的作用及机制尚不清楚。SREBP 通过对多个代谢步骤的综合性调控成为脂代谢的核心调控因子。本研究组对SREBP1的系列研究，发现SREBP1是胰腺癌预后危险因子，SREBP1对胰腺癌细胞生长的调节作用依赖于脂质新生代谢途径。此外我们发现胰腺癌伴糖尿病患者中transgelin-2的表达显著增加，并且与SREBP1表达呈正相关。进一步研究我们发现在胰岛素作用下SREBP1可靶向TAGLN2基因的启动子-2562 / -2552bp区域，并促进其表达transgelin-2，从而促进胰腺癌的生长。此外研究发现KRAS-ERK信号通路可调节transgelin-2的蛋白稳定性，KRAS促进了ERK 对 transgelin-2 的 S145 位点的磷酸化修饰作用，从而调节transgelin-2的蛋白稳定性，促进胰腺癌细胞增殖。进一步通过免疫组化发现transgelin-2的S145磷酸化是胰腺的潜在预后指标。上述研究表明SREBP1、transgelin-2在胰腺癌发生发展及预后中起重要作用；揭示了 SREBP1通过调节脂代谢重编程发挥抑癌作用的机制；阐明了胰岛素通过SREBP1促进transgelin-2表达在糖尿病相关胰腺癌发生发展的新机制；阐述了KRAS经ERK介导transeglin-2磷酸化在胰腺癌发展中的重要作用及调节机制。或为我们理解糖尿病相关性胰腺癌的发生发展提供重要的线索，为胰腺癌的诊治提供了新的靶点。本项目已发表标注基金项目资助和项目批准号的论文3篇，与本项目相关未标注论文1篇，尚有文章正在投稿中。研究成果主要发表于 J EXP CLIN CANC RES (IF: 7.068 分，引用:5次)和 ONCOL LETT (IF:2.311 分，引用:4 次)杂志。本项目联合培养博士1名，硕士2名。