The role of NTS/NTSR1 signal in pancreatic cancer progression

Pancreatic cancer is one of the uncurable cancers and 5-year survival rate is still under 10 %. Therefore, it is urgent to identify a new molecular target for cure. In this study, the mouse serial transplantations by pancreatic orthotopic inoculation model were utilized for screening of new targets. The gene expression of highly malignant cancer cell lines, established in our previous study, showed increased expression of neurotensin receptor-1 (NTSR1). Re-analysis of clinical databases revealed that its expression was higher in pancreatic cancer dependent upon its stage. Overexpression of NTSR1 in SUIT-2 and Panc-1 cells accelerated tumorigenic and metastatic ability in vivo. RNA-sequence analysis revealed that MAPK and NF-kB signaling pathway were activated with neurotensin (NTS) stimulation in highly malignant cancer cell lines from Panc-1 cells. Moreover, NTS induced not only MMP-9, but also CTGF and other pro-inflammatory cytokines and chemokines. Administration of SR48692, a selective antagonist for NTSR1, suppressed tumorigenicity in vivo. These data suggested that NTSR1 can be a diagnostic marker and a new molecular target for pancreatic cancer treatment. Target genes for NTS in highly malignant Panc-1- cells were identified.

胰腺癌是一类难以治愈的恶性肿瘤，其5年生存率仍不足10%，因此亟需发掘用于胰腺癌治愈的新型分子靶点。本研究采用小鼠胰腺癌原位接种连续移植模型，用于新型治疗靶点的筛选。我们既往研究中建立的高恶性胰腺癌细胞系，其基因表达谱显示神经降压素受体1（neurotensin receptor-1, NTSR1）的表达显著上调。对临床数据库的重新分析表明，NTSR1的表达水平随胰腺癌分期进展而升高。在SUIT-2与Panc-1细胞中过表达NTSR1，可增强其体内成瘤与转移能力。RNA测序分析显示，在源自Panc-1细胞的高恶性胰腺癌细胞系中，经神经降压素（neurotensin, NTS）刺激后，丝裂原活化蛋白激酶（mitogen-activated protein kinase, MAPK）与核因子κB（nuclear factor kappa B, NF-κB）信号通路被激活。此外，NTS不仅可诱导基质金属蛋白酶9（matrix metalloproteinase-9, MMP-9）的表达，还可上调结缔组织生长因子（connective tissue growth factor, CTGF）以及其他促炎细胞因子与趋化因子的表达。使用NTSR1的选择性拮抗剂SR48692进行干预，可抑制体内肿瘤的发生发展。上述实验结果表明，NTSR1可作为胰腺癌的诊断标志物与新型治疗分子靶点。本研究同时鉴定了高恶性Panc-1细胞中NTS的靶基因。