Hypoxia differentially regulated CXCR4 and CXCR7 signaling in colon cancer.
Fiche publication
Date publication
janvier 2014
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GALZI Jean-Luc, Dr GUENOT Dominique, Dr PENCREACH Erwan, Pr ROHR Serge, Dr ROMAIN Benoit, Pr BRIGAND Cécile
Tous les auteurs :
Romain B, Hachet-Haas M, Rohr S, Brigand C, Galzi JL, Gaub MP, Pencreach E, Guenot D
Lien Pubmed
Résumé
BACKGROUND: HIF-1alpha and CXCR4/CXCL12 have crucial roles in the metastatic process of colorectal cancer. Our aim was to study the significance of targeting HIF-1alpha and the CXCR4/CXCL12 axis in colorectal cancer to prevent the dissemination process in vitro. METHODS: We investigated CXCR4 and CXCR7 mRNA and protein expression in human colon carcinomas and the modulation of their expression by hypoxia and HIF-1alpha in colon cancer cell lines. The migration of tumor cells in a Boyden chamber was studied after CXCR4 inhibition with siRNA or the CXCR4/CXCL12 neutraligand, chalcone 4. RESULTS: Analysis of a cohort of colon polyps and chromosome-unstable carcinomas showed that the expression of CXCR4 and CXCR7 was similar to that of the normal mucosa in the polyps and early-stage carcinomas but significantly increased in late stage carcinomas. Our data demonstrate that hypoxia strongly induced the expression of CXCR4 transcript and protein at the cell membrane, both regulated by HIF-1alpha, whereas CXCR7 expression was independent of hypoxia. After transient hypoxia, CXCR4 levels remained stable at the cell membrane up to 48 hours. Furthermore, reducing CXCR4 expression impaired CXCL12-induced Akt phosphorylation, whereas Erk activation remained unchanged. In contrast, reducing CXCR7 expression did not affect Akt nor Erk activation. In the presence of CXCR4 or CXCR7 siRNAs, a significant reduction in cell migration occurred (37% and 17%, respectively). Although irinotecan inhibited cell migration by 20% (p
Référence
Mol Cancer. 2014 Mar 14;13:58