CXCR7 contributes to the aggressive phenotype of cholangiocarcinoma cells

Alessandra Gentilini, Alessandra Caligiuri, Chiara Raggi, Krista Rombouts, Massimo Pinzani, Giulia Lori, Margherita Correnti, Pietro Invernizzi, Elisabetta Rovida, Nadia Navari, Sabina Di Matteo, Domenico Alvaro, Jesus M Banales, Pedro Rodrigues, Carlotta Raschioni, Matteo Donadon, Luca Di Tommaso, Fabio Marra

Research output: Contribution to journalArticlepeer-review

Abstract

Development of cholangiocarcinoma (CCA) is dependent on a cross-talk with stromal cells, which release different chemokines including CXCL12, that interacts with two different receptors, CXCR4 and CXCR7. The aim of the present study was to investigate the role of CXCR7 in CCA cells. CXCR7 is overexpressed by different CCA cell lines and in human CCA specimens. Knock-down of CXCR7 in HuCCT-1 cells reduced migration, invasion, and CXCL12-induced adhesion to collagen I. Survival of CCA was also reduced in CXCR7-silenced cells. The ability of CXCL12 to induce cell migration and survival was also blocked by CCX733, a CXCR7 antagonist. Similar effects of CXCR7 activation were observed in CCLP-1 cells and in primary iCCA cells. Enrichment of tumor stem-like cells by a 3D culture system resulted in increased CXCR7 expression compared to cells grown in monolayers, and genetic knockdown of CXCR7 robustly reduced sphere formation both in HuCCT-1 and in CCLP-1 cells. In HuCCT-1 cells CXCR7 was found to interact with β-arrestin 2, which was necessary to mediate CXCL12-induced migration, but not survival. In conclusion, CXCR7 is widely expressed in CCA, and contributes to the aggressive phenotype of CCA cells, inducing cell migration, invasion, adhesion, survival, growth and stem cell-like features. Cell migration induced by CXCR7 requires interaction with β-arrestin 2.

Original languageEnglish
Pages (from-to)2246-2256
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1865
Issue number9
DOIs
Publication statusPublished - Sep 1 2019

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