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dc.contributor.authorCole, Claire L
dc.contributor.authorRushton, Graham
dc.contributor.authorJayson, Gordon C
dc.contributor.authorAvizienyte, Egle
dc.date.accessioned2014-07-08T14:10:05Z
dc.date.available2014-07-08T14:10:05Z
dc.date.issued2014-04-11
dc.identifier.citationOvarian cancer cell heparan sulfate 6-O-sulfotransferases regulate an angiogenic program induced by heparin-binding epidermal growth factor (EGF)-like growth factor/EGF receptor signaling. 2014, 289 (15):10488-501 J Biol Chemen
dc.identifier.issn1083-351X
dc.identifier.pmid24563483
dc.identifier.doi10.1074/jbc.M113.534263
dc.identifier.urihttp://hdl.handle.net/10541/322603
dc.description.abstractHeparan sulfate (HS) is a component of cell surface and extracellular matrix proteoglycans that regulates numerous signaling pathways by binding and activating multiple growth factors and chemokines. The amount and pattern of HS sulfation are key determinants for the assembly of the trimolecular, HS-growth factor-receptor, signaling complex. Here we demonstrate that HS 6-O-sulfotransferases 1 and 2 (HS6ST-1 and HS6ST-2), which perform sulfation at 6-O position in glucosamine in HS, impact ovarian cancer angiogenesis through the HS-dependent HB-EGF/EGFR axis that subsequently modulates the expression of multiple angiogenic cytokines. Down-regulation of HS6ST-1 or HS6ST-2 in human ovarian cancer cell lines results in 30-50% reduction in glucosamine 6-O-sulfate levels in HS, impairing HB-EGF-dependent EGFR signaling and diminishing FGF2, IL-6, and IL-8 mRNA and protein levels in cancer cells. These cancer cell-related changes reduce endothelial cell signaling and tubule formation in vitro. In vivo, the development of subcutaneous tumor nodules with reduced 6-O-sulfation is significantly delayed at the initial stages of tumor establishment with further reduction in angiogenesis occurring throughout tumor growth. Our results show that in addition to the critical role that 6-O-sulfate moieties play in angiogenic cytokine activation, HS 6-O-sulfation level, determined by the expression of HS6ST isoforms in ovarian cancer cells, is a major regulator of angiogenic program in ovarian cancer cells impacting HB-EGF signaling and subsequent expression of angiogenic cytokines by cancer cells.
dc.language.isoenen
dc.rightsArchived with thanks to The Journal of biological chemistryen
dc.subject.meshAnimals
dc.subject.meshAntigens, CD31
dc.subject.meshCell Line, Tumor
dc.subject.meshCulture Media, Conditioned
dc.subject.meshCytokines
dc.subject.meshDisaccharides
dc.subject.meshEpidermal Growth Factor
dc.subject.meshFemale
dc.subject.meshFibroblast Growth Factor 2
dc.subject.meshGene Expression Regulation, Enzymologic
dc.subject.meshGene Expression Regulation, Neoplastic
dc.subject.meshGlucosamine
dc.subject.meshHumans
dc.subject.meshInterleukin-6
dc.subject.meshInterleukin-8
dc.subject.meshMice
dc.subject.meshMice, Inbred NOD
dc.subject.meshNeoplasm Transplantation
dc.subject.meshNeovascularization, Pathologic
dc.subject.meshOvarian Neoplasms
dc.subject.meshReceptor, Epidermal Growth Factor
dc.subject.meshSignal Transduction
dc.subject.meshSulfotransferases
dc.titleOvarian cancer cell heparan sulfate 6-O-sulfotransferases regulate an angiogenic program induced by heparin-binding epidermal growth factor (EGF)-like growth factor/EGF receptor signaling.en
dc.typeArticleen
dc.contributor.departmentFrom the Institute of Cancer Sciences, Faculty of Medical and Human Sciences, The University of Manchester, Manchester M20 4BX, United Kingdom.en
dc.identifier.journalThe Journal of Biological Chemistryen
html.description.abstractHeparan sulfate (HS) is a component of cell surface and extracellular matrix proteoglycans that regulates numerous signaling pathways by binding and activating multiple growth factors and chemokines. The amount and pattern of HS sulfation are key determinants for the assembly of the trimolecular, HS-growth factor-receptor, signaling complex. Here we demonstrate that HS 6-O-sulfotransferases 1 and 2 (HS6ST-1 and HS6ST-2), which perform sulfation at 6-O position in glucosamine in HS, impact ovarian cancer angiogenesis through the HS-dependent HB-EGF/EGFR axis that subsequently modulates the expression of multiple angiogenic cytokines. Down-regulation of HS6ST-1 or HS6ST-2 in human ovarian cancer cell lines results in 30-50% reduction in glucosamine 6-O-sulfate levels in HS, impairing HB-EGF-dependent EGFR signaling and diminishing FGF2, IL-6, and IL-8 mRNA and protein levels in cancer cells. These cancer cell-related changes reduce endothelial cell signaling and tubule formation in vitro. In vivo, the development of subcutaneous tumor nodules with reduced 6-O-sulfation is significantly delayed at the initial stages of tumor establishment with further reduction in angiogenesis occurring throughout tumor growth. Our results show that in addition to the critical role that 6-O-sulfate moieties play in angiogenic cytokine activation, HS 6-O-sulfation level, determined by the expression of HS6ST isoforms in ovarian cancer cells, is a major regulator of angiogenic program in ovarian cancer cells impacting HB-EGF signaling and subsequent expression of angiogenic cytokines by cancer cells.


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