Pancreatic stellate cells contribute pancreatic cancer pain via activation of sHH signaling pathway.
Pancreatic stellate cells contribute pancreatic cancer pain via activation of sHH signaling pathway.
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胰腺星状细胞通过激活 sHH 信号通路导致胰腺癌疼痛
DOI：
10.18632/oncotarget.7776
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发表时间：
2016-04-05
期刊：
影响因子：
--
通讯作者：
Ma Z
中科院分区：
文献类型：
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作者：
Han L;Ma J;Duan W;Zhang L;Yu S;Xu Q;Lei J;Li X;Wang Z;Wu Z;Huang JH;Wu E;Ma Q;Ma Z
腹痛是胰腺癌（PC）的重要临床症状，影响PC患者的生活质量。然而，PC疼痛的发病机制在很大程度上是未知的。在这项研究中，我们发现PC疼痛是由胰腺星状细胞（PSCs）中的音刺猬（sHH）信号通路启动的，该信号通路被PC细胞分泌的sHH激活，然后，来自PSCs的神经营养因子介导疼痛。建立不同的体外培养体系，检测sHH通路分子、神经营养因子、TRPV1和疼痛因子的表达。采用膜片钳技术观察辣椒素诱发背根神经节（DRG）神经元TRPV1电流。在原位肿瘤模型中观察到疼痛相关行为。sHH和PSC通过在共培养系统中诱导NGF和BDNF增加TRPV1、SP和CGRP的表达和分泌，也增加TRPV1电流。而抑制sHH通路或NGF则可降低TRPV1、SP和CGRP的表达。在体内，高水平表达sHH的PSC和PC细胞可以增强疼痛行为。此外，与对照组相比，NGF或TRPV1的阻断显著减弱了对机械刺激的疼痛反应。我们的研究结果表明sHH信号通路参与了PC痛的发生，PSC通过诱导NGF在此过程中发挥重要作用。
Abdominal pain is a critical clinical symptom in pancreatic cancer (PC) that affects the quality of life for PC patients. However, the pathogenesis of PC pain is largely unknown. In this study, we show that PC pain is initiated by the sonic hedgehog (sHH) signaling pathway in pancreatic stellate cells (PSCs), which is activated by sHH secreted from PC cells, and then, neurotrophic factors derived from PSCs mediate the pain. The different culture systems were established in vitro, and the expression of sHH pathway molecules, neurotrophic factors, TRPV1, and pain factors were examined. Capsaicin-evoked TRPV1 currents in dorsal root ganglion (DRG) neurons were examined by the patch-clamp technique. Pain-related behavior was observed in an orthotopic tumor model. sHH and PSCs increased the expression and secretion of TRPV1, SP, and CGRP by inducing NGF and BDNF in a co-culture system, also increasing TRPV1 current. But, suppressing sHH pathway or NGF reduced the expression of TRPV1, SP, and CGRP. In vivo, PSCs and PC cells that expressed high levels of sHH could enhance pain behavior. Furthermore, the blockade of NGF or TRPV1 significantly attenuated the pain response to mechanical stimulation compared with the control. Our results demonstrate that sHH signaling pathway is involved in PC pain, and PSCs play an essential role in the process greatly by inducing NGF.