Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/134640
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Type: | Journal article |
Title: | Sphingosine Kinase-1 is Overexpressed and Correlates with Hypoxia in Osteosarcoma: Relationship with Clinicopathological Parameters |
Author: | Gomez-Brouchet, A. Illac, C. Ledoux, A. Fortin, P.Y. de Barros, S. Vabre, C. Despas, F. Peries, S. Casaroli, C. Bouvier, C. Aubert, S. de Pinieux, G. Larousserie, F. Galmiche, L. Talmont, F. Pitson, S. Maddelein, M.L. Cuvillier, O. |
Citation: | Cancers, 2022; 14(3):499-1-499-17 |
Publisher: | MDPI |
Issue Date: | 2022 |
ISSN: | 2072-6694 2072-6694 |
Statement of Responsibility: | Anne Gomez-Brouchet, Claire Illac, Adeline Ledoux, Pierre-Yves Fortin, Sandra de Barros, Clémentine Vabre, Fabien Despas, Sophie Peries, Christelle Casaroli, Corinne Bouvier, Sébastien Aubert, Gonzague de Pinieux, Frédérique Larousserie, Louise Galmiche, Franck Talmont, Stuart Pitson, Marie-Lise Maddelein and Olivier Cuvillier |
Abstract: | The Sphingosine kinase-1/Sphingosine 1-Phosphate (SphK1/S1P) signaling pathway is overexpressed in various cancers, and is instrumental for the adaptation to hypoxia in a number of solid tumor models, but no data are available in osteosarcoma. Here we report that SphK1 and the S1P1 receptor are involved in HIF-1α accumulation in hypoxic osteosarcoma cells. FTY720 (Fingolimod), which targets SphK1 and S1P1, prevented HIF-1α accumulation, and also inhibited cell proliferation in both normoxia and hypoxia unlike conventional chemotherapy. In human biopsies, a significant increase of SphK1 activity was observed in cancer compared with normal bones. In all sets of TMA samples (130 cases of osteosarcoma), immunohistochemical analysis showed the hypoxic marker GLUT-1, SphK1 and S1P1 were expressed in tumors. SphK1 correlated with the GLUT-1 suggesting that SphK1 is overexpressed and correlates with intratumoral hypoxia. No correlation was found between GLUT-1 or SphK1 and response to chemotherapy, but a statistical difference was found with increased S1P1 expression in patients with poor response in long bone osteosarcomas. Importantly, multivariate analyses showed that GLUT-1 was associated with an increased risk of death in flat bone, whereas SphK1 and S1P1 were associated with an increased risk of death in long bones. |
Keywords: | FTY720; fingolimod; sphingosine kinase; S1P1; osteosarcoma; HIF; GLUT-1 |
Rights: | © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). |
DOI: | 10.3390/cancers14030499 |
Published version: | http://dx.doi.org/10.3390/cancers14030499 |
Appears in Collections: | Molecular and Biomedical Science publications |
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hdl_134640.pdf | Published version | 1.84 MB | Adobe PDF | View/Open |
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