title: CXCR7 is up-regulated in human and murine hepatocellular carcinoma and is specifically expressed by endothelial cells.
abstract: Development of hepatocellular carcinoma (HCC) is a complex and progressive disease that involves cycles of liver cell death, inflammation, and tissue regeneration/remodelling. Chemokines and chemokine receptors play numerous and integral roles in the disease progression of HCC. Here we investigated the novel chemokine receptor CXCR7/RDC1 in HCC progression, its two known ligands CXCL12 and CXCL11, as well as the other CXCL12 receptor, CXCR4. Our results show that in a cohort of 408 human HCCs, CXCR7 and CXCL11 were significantly higher in tumours compared to normal liver controls (5- and 10-fold, respectively). Immunohistochemical (IHC) staining on human HCC sections confirmed that both CXCL11 and CXCR7 were much higher in cancer tissues. Furthermore, IHC staining revealed that CXCR7 protein was only expressed in endothelial cells whereas CXCL11 exhibited a much broader tissue expression. At the cellular level we observed that in vitro, human microvascular endothelial cells (HMEC-1) up-regulated CXCR7 under hypoxic and acidic pH conditions, which are well known characteristics of the HCC tumour micro-environment. As for its ligand, we observed that IFNγ robustly induced CXCL11 in hepatic stellate cells, hepatocytes, and HMEC-1s. In addition, in the mouse Diethylnitrosamine model of hepatocarcinogenesis we observed a very strong induction of CXCR7 and CXCL11 transcripts, confirming that CXCR7/CXCL11 up-regulation is conserved between human and mice liver cancer. Altogether, our results strongly support the hypothesis that the CXCL11/CXCR7 pathway is involved HCC progression.
authors.affiliation: EA 4427 SeRAIC-IRSET, Université de Rennes 1, IFR 140 Rennes, France.
authors.forename: Justin
authors.initials: J
authors.lastname: Monnier
authors.forename: Mathieu
authors.initials: M
authors.lastname: Boissan
authors.forename: Annie
authors.initials: A
authors.lastname: L'Helgoualc'h
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Lacombe
authors.forename: Bruno
authors.initials: B
authors.lastname: Turlin
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
authors.forename: Nathalie
authors.initials: N
authors.lastname: Théret
authors.forename: Claire
authors.initials: C
authors.lastname: Piquet-Pellorce
authors.forename: Michel
authors.initials: M
authors.lastname: Samson
mesh_terms: D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019169:Jurkat Cells; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009928:Organ Specificity / Q000235:genetics; D054387:Receptors, CXCR / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C501896:ACKR3 protein, human; C501897:Cmkor1 protein, mouse; D054387:Receptors, CXCR