Research Papers:

Trypsin-protease activated receptor-2 signaling contributes to pancreatic cancer pain

Jiao Zhu, Xue-Rong Miao, Kun-Ming Tao, Hai Zhu, Zhi-Yun Liu, Da-Wei Yu, Qian-Bo Chen, Hai-Bo Qiu and Zhi-Jie Lu _

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Oncotarget. 2017; 8:61810-61823. https://doi.org/10.18632/oncotarget.18696

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Jiao Zhu1,*, Xue-Rong Miao1,*, Kun-Ming Tao1,*, Hai Zhu2, Zhi-Yun Liu1, Da-Wei Yu3, Qian-Bo Chen1, Hai-Bo Qiu1 and Zhi-Jie Lu1

1Department of Anesthesiology and Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China

2Department of Anesthesiology, Maternity and Infant Health Hospital of Putuo District, Shanghai 200062, China

3Department of Anesthesiology, No.101 hospital of PLA, Wuxi 214000, China

*These authors have contributed equally to this work

Correspondence to:

Zhi-Jie Lu, email: [email protected]

Keywords: pancreatic cancer, pain, trypsin, protease activated receptor-2, pancreatic cancer pain model

Received: December 12, 2016    Accepted: May 05, 2017    Published: June 27, 2017


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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