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

2.50
Hdl Handle:
http://hdl.handle.net/10547/228928
Title:
WWOX gene expression abolishes ovarian cancer tumorigenicity in vivo and decreases attachment to fibronectin via integrin alpha3.
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
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.
Affiliation:
University of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, United Kingdom.
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
Issue Date:
1-Jun-2009
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
Appears in Collections:
Cell and Cryobiology Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorGourley, Charlieen_GB
dc.contributor.authorPaige, Adam J.W.en_GB
dc.contributor.authorTaylor, Karen J.en_GB
dc.contributor.authorWard, Carolen_GB
dc.contributor.authorKuske, Barbaraen_GB
dc.contributor.authorZhang, Jieqingen_GB
dc.contributor.authorSun, Mingjunen_GB
dc.contributor.authorJanczar, Szymonen_GB
dc.contributor.authorHarrison, David J.en_GB
dc.contributor.authorMuir, Morwennaen_GB
dc.contributor.authorSmyth, John F.en_GB
dc.contributor.authorGabra, Hanien_GB
dc.date.accessioned2012-06-14T11:42:40Zen
dc.date.available2012-06-14T11:42:40Zen
dc.date.issued2009-06-01en
dc.identifier.citationGourley, 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):4835-4842en_GB
dc.identifier.issn1538-7445en
dc.identifier.pmid19458077en
dc.identifier.doi10.1158/0008-5472.CAN-08-2974en
dc.identifier.urihttp://hdl.handle.net/10547/228928en
dc.description.abstractThe 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.en_GB
dc.language.isoenen
dc.publisherAmerican Association for Cancer Researchen_GB
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pubmed/19458077en_GB
dc.relation.urlhttp://cancerres.aacrjournals.org/content/69/11/4835.longen
dc.subject.meshAnimalsen
dc.subject.meshApoptosisen
dc.subject.meshCarcinomaen
dc.subject.meshCell Adhesionen
dc.subject.meshCell Line, Tumoren
dc.subject.meshCell Proliferationen
dc.subject.meshFemaleen
dc.subject.meshFibronectinsen
dc.subject.meshGene Expression Regulation, Neoplasticen
dc.subject.meshIntegrin alpha3en
dc.subject.meshMiceen
dc.subject.meshMice, Nudeen
dc.subject.meshNeoplasm Invasivenessen
dc.subject.meshOvarian Neoplasmsen
dc.subject.meshOxidoreductasesen
dc.subject.meshPeritoneal Neoplasmsen
dc.subject.meshProtein Bindingen
dc.subject.meshTransfectionen
dc.subject.meshTumor Suppressor Proteinsen
dc.subject.meshXenograft Model Antitumor Assaysen
dc.titleWWOX gene expression abolishes ovarian cancer tumorigenicity in vivo and decreases attachment to fibronectin via integrin alpha3.en
dc.typeArticleen
dc.contributor.departmentUniversity of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, United Kingdom.en_GB
dc.identifier.journalCancer researchen_GB

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