Neurotransmitter substance P mediates pancreatic cancer perineural invasion via NK-1R in cancer cells.
Neurotransmitter substance P mediates pancreatic cancer perineural invasion via NK-1R in cancer cells.
复制标题
神经递质 P 物质通过癌细胞中的 NK-1R 介导胰腺癌神经周围侵袭
DOI：
10.1158/1541-7786.mcr-12-0609
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发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
Wu E
中科院分区：
文献类型：
--
作者：
Li X;Ma G;Ma Q;Li W;Liu J;Han L;Duan W;Xu Q;Liu H;Wang Z;Sun Q;Wang F;Wu E
胰腺癌严重的腹痛严重影响患者的生活质量。然而，其内在机制尚不清楚。本研究旨在探讨P物质（Substance P，SP）与胰腺癌神经浸润（perineural invasion，PNI）的关系以及SP介导胰腺癌PNI的机制。采用定量PCR和Western blotting方法检测胰腺癌细胞和新生大鼠背根神经节（DRG）细胞中SP和NK-1 R的表达。MTT法检测SP对胰腺癌细胞增殖的影响; Transwell Matrigel侵袭实验检测SP对胰腺癌细胞侵袭的影响。通过模拟体内肿瘤/神经元相互作用的共培养系统来评估胰腺癌细胞的神经嗜性的改变。SP不仅广泛分布于新生DRG的突起生长中，而且在MIA PaCa-2和BxPC-3细胞中也有表达。发现NK-1 R在检查的胰腺癌细胞系中过表达。SP诱导胰腺癌细胞增殖和侵袭以及基质金属蛋白酶（MMP）-2的表达，NK-1 R拮抗剂抑制这些作用。此外，SP促进神经突起生长和胰腺癌细胞簇向DRG的迁移，这在共培养模型中被NK-1 R拮抗剂阻断。提示SP在胰腺癌转移和PNI的发生发展中起重要作用，阻断SP/NK-1 R信号系统是胰腺癌治疗的新策略。Mol Cancer Res; 11（3）; 294-302.©2012 AACR。
Pancreatic cancer significantly affects the quality of life due to the severe abdominal pain. However, the underlying mechanism is not clear. This study aimed to determine the relationship between Substance P (SP) and pancreatic cancer perineural invasion (PNI) as well as the mechanism of SP mediating pancreatic cancer PNI, which causes pain in patients with pancreatic cancer. Human pancreatic cancer cells and newborn dorsal root ganglions (DRG) were used to determine the expression of SP or NK-1R in pancreatic cancer cells and DRGs cells by QT-PCR and Western blotting. The effects of SP on pancreatic cancer cell proliferation and invasion were analyzed using MTT assay and Transwell Matrigel invasion assay, respectively. Alterations in the neurotropism of pancreatic cancer cells were assessed by coculture system, which mimics the interaction of tumor/neuron in vivo. SP is not only widely distributed in the neurite outgrowth from newborn DRGs but also expressed in MIA PaCa-2 and BxPC-3 cells. NK-1R is found to be overexpressed in the pancreatic cancer cell lines examined. SP induces cancer cell proliferation and invasion as well as the expression of matrix metalloproteinase (MMP)-2 in pancreatic cancer cells, and NK-1R antagonists inhibit these effects. Furthermore, SP promotes neurite outgrowth and the migration of pancreatic cancer cell cluster to the DRGs, which is blocked by NK-1R antagonists in the coculture model. Our results suggest that SP plays an important role in the development of pancreatic cancer metastasis and PNI, and blocking the SP/NK-1R signaling system is a novel strategy for the treatment of pancreatic cancer. Mol Cancer Res; 11(3); 294–302. ©2012 AACR.