核蛋白易位启动子区域蛋白TPR在胰腺导管腺癌发生发展中的作用及其机制

胰腺癌是一种诊治困难的消化系统肿瘤，而胰腺导管腺癌在其中占了90%。核蛋白易位启动子区域蛋白TPR在肿瘤的发生发展过程中发挥着重要的作用，而TPR在胰腺癌中的作用及相关分子机制至今为止仍不清楚。申请人通过分析GEO和TCGA等数据库以及胰腺癌组织芯片发现TPR在胰腺导管腺癌中表达显著上调，且与预后密切相关。通过体内外实验，并发现干扰TPR可以抑制胰腺导管腺癌细胞的增殖和克隆形成，以及胰腺导管腺癌细胞在裸鼠皮下和小鼠胰腺原位的生长。进一步的研究发现TPR与KDM5A存在相互作用，TPR能够增强肿瘤细胞的核苷酸代谢，从而促进胰腺导管腺癌细胞的生长。之后申请人拟在胰腺癌KPC模型小鼠中进行验证，并结合临床样本分析TPR的临床意义及其作为治疗靶点的可能性。本课题将从肿瘤的代谢重编程方面着手为改善胰腺癌的诊疗提供新的思路和方法。

Pancreatic cancer is a kind of digestive system cancer and is difficult to diagnose and treat. Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of them. Translocated Promoter Region Protein (TPR) plays an important role in the development of tumor. However, the role and related molecular mechanism of TPR in pancreatic cancer are still unclear. By analyzing GEO/TCGA databases and pancreatic cancer tissue microarray, we found that TPR expression was significantly up-regulated in PDAC and closely related to patient prognosis. Through in vitro and in vivo experiments, it was found that knockdown of TPR could inhibit the proliferation and colony formation of PDAC cells, and the subcutaneous or orthotopic growth of PDAC cells in mice. Further study indicated that TPR interacts with KDM5A, and enhances the nucleotide metabolism of tumor cells, thus promotes the growth of PDAC cells. Furthermore, we will use pancreatic cancer model KPC mice to confirm above results, and analyze the clinical significance of TPR and the possibility of it as a therapeutic target. This project will provide new ideas and methods for improving the diagnosis and treatment of pancreatic cancer from the way of tumor metabolic reprogramming.