Trypsin-protease activated receptor-2 signaling contributes to pancreatic cancer pain.
Trypsin-protease activated receptor-2 signaling contributes to pancreatic cancer pain.
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胰蛋白酶激活的受体 2 信号传导导致胰腺癌疼痛。
DOI：
10.18632/oncotarget.18696
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发表时间：
2017-09-22
期刊：
影响因子：
--
通讯作者：
Lu ZJ
中科院分区：
文献类型：
--
作者：
Zhu J;Miao XR;Tao KM;Zhu H;Liu ZY;Yu DW;Chen QB;Qiu HB;Lu ZJ
疼痛治疗是胰腺癌患者临床护理的一个重要方面。本研究探讨胰蛋白酶活化受体-2 （PAR-2）在胰腺癌疼痛中的作用。从胰腺癌患者（n=22）和对照患者（n=22）中收集胰腺组织样本。免疫荧光分析证实了PAR-2和神经元标记物在胰腺癌组织中的共定位。胰蛋白酶水平和蛋白酶活性在胰腺癌组织标本中高于对照组。培养的人胰腺癌组织上清液（PC上清液）诱导背根神经节（DRG）神经元释放P物质和降钙素基因相关肽，而选择性PAR-2拮抗剂FS-NH2可抑制这一作用。我们采用BALB/c裸小鼠原位肿瘤模型来证实PAR-2信号在胰腺癌内脏疼痛中的作用，并采用雄性Sprague-Dawley大鼠来评估动态疼痛。FS-NH2治疗降低了荷瘤小鼠的预感评分、机械性痛觉过敏和内脏运动反射反应。大鼠皮下注射PC上清液诱导疼痛行为，经FS-NH2或FUT-175（一种广谱丝氨酸蛋白酶抑制剂）处理后疼痛减轻。我们的研究结果表明胰蛋白酶- par -2信号传导有助于体内胰腺癌疼痛。针对PAR-2或其下游信号分子的治疗策略可能有效缓解胰腺癌疼痛。
Pain treatment is a critical aspect of pancreatic cancer patient clinical care. This study investigated the role of trypsin-protease activated receptor-2 (PAR-2) in pancreatic cancer pain. Pancreatic tissue samples were collected from pancreatic cancer (n=22) and control patients (n=22). Immunofluorescence analyses confirmed colocalization of PAR-2 and neuronal markers in pancreatic cancer tissues. Trypsin levels and protease activities were higher in pancreatic cancer tissue specimens than in the controls. Supernatants from cultured human pancreatic cancer tissues (PC supernatants) induced substance P and calcitonin gene-related peptide release in dorsal root ganglia (DRG) neurons, and FS-NH2, a selective PAR-2 antagonist, inhibited this effect. A BALB/c nude mouse orthotopic tumor model was used to confirm the role of PAR-2 signaling in pancreatic cancer visceral pain, and male Sprague-Dawley rats were used to assess ambulatory pain. FS-NH2 treatment decreased hunch scores, mechanical hyperalgesia, and visceromotor reflex responses in tumor-bearing mice. In rats, subcutaneous injection of PC supernatant induced pain behavior, which was alleviated by treatment with FS-NH2 or FUT-175, a broad-spectrum serine protease inhibitor. Our findings suggest that trypsin-PAR-2 signaling contributes to pancreatic cancer pain in vivo. Treatment strategies targeting PAR-2 or its downstream signaling molecules might effectively relieve pancreatic cancer pain.
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