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    WWOX gene expression abolishes ovarian cancer tumorigenicity in vivo and decreases attachment to fibronectin via integrin alpha3.

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    Authors
    Gourley, Charlie
    Paige, Adam J.W.
    Taylor, Karen J.
    Ward, Carol
    Kuske, Barbara
    Zhang, Jieqing
    Sun, Mingjun
    Janczar, Szymon
    Harrison, David J.
    Muir, Morwenna
    Smyth, John F.
    Gabra, Hani
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    Affiliation
    University of Edinburgh Cancer Research Centre
    Issue Date
    2009-06-01
    
    Metadata
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    Abstract
    The WW domain-containing oxidoreductase (WWOX) gene is located at FRA16D, a common fragile site involved in human cancer. Targeted deletion of Wwox in mice causes increased spontaneous tumor incidence, confirming that WWOX is a bona fide tumor suppressor gene. We show that stable transfection of WWOX into human PEO1 ovarian cancer cells, containing homozygous WWOX deletion, abolishes in vivo tumorigenicity, but this does not correlate with alteration of in vitro growth. Rather, WWOX restoration in PEO1, or WWOX overexpression in SKOV3 ovarian cancer cells, results in reduced attachment and migration on fibronectin, an extracellular matrix component linked to peritoneal metastasis. Conversely, siRNA-mediated knockdown of endogenous WWOX in A2780 ovarian cancer cells increases adhesion to fibronectin. In addition, whereas there is no WWOX-dependent difference in cell death in adherent cells, WWOX-transfected cells in suspension culture display a proapoptotic phenotype. We further show that WWOX expression reduces membranous integrin alpha(3) protein but not integrin alpha(3) mRNA levels, and that adhesion of PEO1 cells to fibronectin is predominantly mediated through integrin alpha(3). We therefore propose that WWOX acts as an ovarian tumor suppressor by modulating the interaction between tumor cells and the extracellular matrix and by inducing apoptosis in detached cells. Consistent with this, the suppression of PEO1 tumorigenicity by WWOX can be partially overcome by implanting these tumor cells in Matrigel. These data suggest a possible role for the loss of WWOX in the peritoneal dissemination of human ovarian cancer cells.
    Citation
    Gourley, C. et al (2009) 'WWOX gene expression abolishes ovarian cancer tumorigenicity in vivo and decreases attachment to fibronectin via integrin alpha3' Cancer Res. 69 (11):4835-4842
    Publisher
    American Association for Cancer Research
    Journal
    Cancer research
    URI
    http://hdl.handle.net/10547/228928
    DOI
    10.1158/0008-5472.CAN-08-2974
    PubMed ID
    19458077
    Additional Links
    http://www.ncbi.nlm.nih.gov/pubmed/19458077
    http://cancerres.aacrjournals.org/content/69/11/4835.long
    Type
    Article
    Language
    en
    ISSN
    1538-7445
    ae974a485f413a2113503eed53cd6c53
    10.1158/0008-5472.CAN-08-2974
    Scopus Count
    Collections
    Cell and Cryobiology Research Group

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