Interaction of the Sympathetic Nerve with Pancreatic Cancer Cells Promotes Perineural Invasion through the Activation of STAT3 Signaling
Interaction of the Sympathetic Nerve with Pancreatic Cancer Cells Promotes Perineural Invasion through the Activation of STAT3 Signaling
复制标题
DOI：
10.1158/1535-7163.mct-12-0809
复制
发表时间：
2013-03-01
影响因子：
5.7
通讯作者：
Xie, Keping
中科院分区：
文献类型：
--
作者：
Guo, Kun;Ma, Qingyong;Xie, Keping
周围神经侵袭(PNI)是胰腺癌局部复发和生存不良的重要原因之一。然而，PNI的确切机制仍不清楚。在这项研究中，我们试图确定交感神经和胰腺癌细胞之间的相互信号相互作用及其潜在的机制。我们利用体外共培养的小鼠背根神经节和胰腺癌细胞、细胞和分子生物学以及动物模型来评价交感神经递质去甲肾上腺素(NE)在PNI进展和发病机制中的作用。NE以浓度依赖的方式促进胰腺癌细胞PNI和磷酸化STAT3水平的升高。NE介导的STAT3激活可通过阻断β-肾上腺素能受体(AR)和阻断蛋白激酶A来抑制，但不能通过阻断α-AR来抑制。阻断STAT3可以抑制NE诱导的NGF、MMP2和MMP9的表达，并减弱胰腺癌细胞的迁移、侵袭能力和PNI。此外，体内应用STAT3磷酸化抑制剂可阻断胰腺癌细胞的PNI。这些研究表明，NE通过β-AR/PKA/STAT3信号通路在胰腺癌PNI的发生发展中起关键作用。交感神经和胰腺癌细胞之间的相互信号相互作用在胰腺癌PNI的发病机制中起重要作用。抑制交感神经活性或STAT3可能是胰腺癌PNI治疗的潜在策略。摩尔癌症治疗；12(3)；264-73。(C)2012年AACR。
Perineural invasion (PNI) is one of the most important causes of local recurrence and poor survival in pancreatic cancer. However, the exact mechanism of PNI is still not clear. In this study, we sought to identify the reciprocal signaling interactions between sympathetic nerves and pancreatic cancer cells and the underlying mechanisms. We used mouse dorsal root ganglia and pancreatic cancer cells cocultured in vitro, cellular and molecular biology, and animal models to evaluate the function of the sympathetic neurotransmitter norepinephrine (NE) in PNI progression and pathogenesis. NE promoted PNI of pancreatic cancer cells and increased levels of phosphorylated STAT3 in a concentration-dependent manner. NE-mediated activation of STAT3 was inhibited by blocking beta-adrenergic receptors (AR) and by blocking protein kinase A, but not through blocking alpha-AR. Blocking STAT3 could inhibit NE-induced NGF, MMP2, and MMP9 expression and attenuate the migratory, invasive ability and PNI of pancreatic cancer cells. Furthermore, PNI of pancreatic cancer cells was blocked by treatment with a STAT3 phosphorylation inhibitor in vivo. These studies show that NE plays a critical role in pancreatic cancer PNI development and progression through the beta-AR/PKA/STAT3 signaling pathway. Reciprocal signaling interactions between the sympathetic nerves and pancreatic cancer cells critically contribute to pancreatic cancer PNI pathogenesis. Inhibition of the activity of sympathetic nerves or STAT3 may be potential strategies for pancreatic cancer PNI therapy. Mol Cancer Ther; 12(3); 264-73. (C)2012 AACR.