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Sphingosine kinase-1 is overexpressed and correlates with hypoxia in osteosarcoma: relationship with clinicopathological parameters

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.
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https://hal-cnrs.archives-ouvertes.fr/hal-03312272
Contributor : Olivier Cuvillier Connect in order to contact the contributor
Submitted on : Wednesday, February 9, 2022 - 7:38:28 PM
Last modification on : Tuesday, April 12, 2022 - 9:30:02 AM

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Anne Gomez-Brouchet, Claire Illac, Adeline Ledoux, Pierre-Yves Fortin, Sandra de Barros, et al.. Sphingosine kinase-1 is overexpressed and correlates with hypoxia in osteosarcoma: relationship with clinicopathological parameters. Cancers, MDPI, 2022, 14 (3), pp.499. ⟨10.3390/cancers14030499⟩. ⟨hal-03312272v2⟩

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