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    Ovarian 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.

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    Authors
    Cole, Claire L
    Rushton, Graham
    Jayson, Gordon C
    Avizienyte, Egle
    Affiliation
    From the Institute of Cancer Sciences, Faculty of Medical and Human Sciences, The University of Manchester, Manchester M20 4BX, United Kingdom.
    Issue Date
    2014-04-11
    
    Metadata
    Show full item record
    Abstract
    Heparan 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.
    Citation
    Ovarian 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 Chem
    Journal
    The Journal of Biological Chemistry
    URI
    http://hdl.handle.net/10541/322603
    DOI
    10.1074/jbc.M113.534263
    PubMed ID
    24563483
    Type
    Article
    Language
    en
    ISSN
    1083-351X
    ae974a485f413a2113503eed53cd6c53
    10.1074/jbc.M113.534263
    Scopus Count
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    All Christie Publications

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