CXCL12-CXCR7 axis contributes to the invasive phenotype of pancreatic cancer
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Jun-Chao Guo1,*, Jian Li1,3,*, Li Zhou1,*, Jian-Yu Yang4, Zhi-Gang Zhang5, Zhi-Yong Liang2, Wei-Xun Zhou2, Lei You1, Tai-Ping Zhang1, Yu-Pei Zhao1
1Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China
2Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China
3Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, China
4Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
5State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
*These authors have contributed equally to this work
Yu-Pei Zhao, email: [email protected]
Tai-Ping Zhang, email: [email protected]
Keywords: pancreatic cancer, invasive phenotype, prognosis, CXCL12, CXCR7, mTOR
Received: March 18, 2016 Accepted: July 27, 2016 Published: August 17, 2016
Chemokine (C-X-C motif) receptor 7 (CXCR7) and its ligand, chemokine (C-X-C motif) ligand 12 (CXCL12), were established to be involved in biological behaviors and associated with prognosis in many cancers. However, effects, underlying mechanisms of CXCL12-CXCR7 axis in invasive phenotype of pancreatic cancer (PC) and its clinicopathologic significances have not been comprehensively explored. In the present study, it was first found by tissue microarray-based immunohistochemistry that CXCL12 and CXCR7 staining scores were significantly associated with vessel invasion and overall survival in two independent cohorts of PC. Besides, co-expression of these proteins was an independent prognosticator in multivariate analysis in both cohorts. Then, migration and invasion, but not proliferation, were decreased in CXCR7-stably silenced PC cells, whereas opposite changes were observed in CXCR7-stably overexpressed cells, accompanied by alterations of mTOR and Rho/ROCK pathways. CXCL12 stimulated migration, invasion, CXCR7 expression and phosphorylation of key mTOR proteins. AMD3100 did not influence effects of CXCL12. Two mTOR inhibitors, rapamycin and Torin1, reversed enhanced invasive phenotypes and mTOR phosphorylation in CXCR7-overexpressed cells. Moreover, CXCR7 directly interacts with mTOR. Finally, liver metastasis, but not growth, was affected by CXCR7 status in orthotopically-implanted PC models in nude mice. Collectively, CXCL12-CXCR7 axis accelerates migration and invasion of PC cells through mTOR and Rho/ROCK pathways, and predicts poor prognosis of PC.
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