title: CXCL12-CXCR7 axis contributes to the invasive phenotype of pancreatic cancer.
abstract: 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.
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China.
authors.forename: Jun-Chao
authors.initials: JC
authors.lastname: Guo
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China.|Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Jian-Yu
authors.initials: JY
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Liang
authors.affiliation: Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China.
authors.forename: Wei-Xun
authors.initials: WX
authors.lastname: Zhou
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China.
authors.forename: Lei
authors.initials: L
authors.lastname: You
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China.
authors.forename: Tai-Ping
authors.initials: TP
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China.
authors.forename: Yu-Pei
authors.initials: YP
authors.lastname: Zhao
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001596:Benzylamines; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism; D000080027:Cyclams; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011379:Prognosis; D054387:Receptors, CXCR / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C501896:ACKR3 protein, human; D001596:Benzylamines; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D054387:Receptors, CXCR; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C088327:plerixafor
keywords: CXCL12; CXCR7; invasive phenotype; mTOR; pancreatic cancer; prognosis