Hypoxia differentially regulated CXCR4 and CXCR7 signaling in colon cancerReport as inadecuate




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Molecular Cancer

, 13:58

First Online: 14 March 2014Received: 04 September 2013Accepted: 04 March 2014DOI: 10.1186-1476-4598-13-58

Cite this article as: Romain, B., Hachet-Haas, M., Rohr, S. et al. Mol Cancer 2014 13: 58. doi:10.1186-1476-4598-13-58

Abstract

BackgroundHIF-1α and CXCR4-CXCL12 have crucial roles in the metastatic process of colorectal cancer. Our aim was to study the significance of targeting HIF-1α and the CXCR4-CXCL12 axis in colorectal cancer to prevent the dissemination process in vitro.

MethodsWe investigated CXCR4 and CXCR7 mRNA and protein expression in human colon carcinomas and the modulation of their expression by hypoxia and HIF-1α 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.

ResultsAnalysis 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-1α, 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 <0.001, the irinotecan and chalcone 4 combination further increased inhibition to 40% p <0.001.

ConclusionWe demonstrated, for the first time, that hypoxia upregulated CXCR4 but not CXCR7 expression in tumor cells and that the CXCR4 receptor protein level remains high at the cell membrane when the tumor cells return to normoxia for up to 48 hours. In addition we showed the interest to inhibit the CXCR4 signaling by inhibiting both the HIF-1α and CXCR4-CXCL12 pathway. CXCR4 seems to be a relevant target because it is continuously expressed and functional both in normoxic and hypoxic conditions in tumor cells.

KeywordsChemokines Hypoxia Colon Migration Metastasis Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-13-58 contains supplementary material, which is available to authorized users.

Benoît Romain, Muriel Hachet-Haas contributed equally to this work.

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Author: Benoît Romain - Muriel Hachet-Haas - Serge Rohr - Cécile Brigand - Jean-Luc Galzi - Marie-Pierre Gaub - Erwan Pencreach -

Source: https://link.springer.com/



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