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.
Highlights
It has been well known that pancreatic cancer (PC) carries extremely disappointing overall prognosis, despite fully resected early lesions [1]
Chi-square analysis found that tumoral expressions of CXCL12 and CXCR7 were all significantly associated with vessel invasion in both cohorts (P=0.007 and =0.047 for CXCL12; P=0.022 and =0.003 for CXCR7; Supplementary Tables S1, S2)
In Beijing cohort, CXCL12 expression was related to histological grade (P=0.019; Supplementary Table S1), whereas CXCR7 expression was linked to sex and histological grade in Shanghai cohort (P=0.033 and =0.045; Table S2)
Summary
It has been well known that pancreatic cancer (PC) carries extremely disappointing overall prognosis, despite fully resected early lesions [1]. Molecules and mechanisms relative to invasion and dissemination of PC cells are long of interest. Except for classical signaling pathways involved in pancreatic tumorigenesis, for example, Ras-ERK pathway [3], www.impactjournals.com/oncotarget many genes/proteins, such as NOP14 [4, 5], DCLK1 [5], interleukin-22/interleukin-22 receptor [6], FoxQ1 [7], CHIP [8] and microRNAs [9], were recently found to play important roles in migration and invasion of PC cells. Further data concerning exact mechanisms and more candidates remain to be accumulated
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