title: WWOX gene expression abolishes ovarian cancer tumorigenicity in vivo and decreases attachment to fibronectin via integrin alpha3.
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.
authors.affiliation: University of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Charlie
authors.initials: C
authors.lastname: Gourley
authors.forename: Adam J W
authors.initials: AJ
authors.lastname: Paige
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Taylor
authors.forename: Carol
authors.initials: C
authors.lastname: Ward
authors.forename: Barbara
authors.initials: B
authors.lastname: Kuske
authors.forename: Jieqing
authors.initials: J
authors.lastname: Zhang
authors.forename: Mingjun
authors.initials: M
authors.lastname: Sun
authors.forename: Szymon
authors.initials: S
authors.lastname: Janczar
authors.forename: David J
authors.initials: DJ
authors.lastname: Harrison
authors.forename: Morwenna
authors.initials: M
authors.lastname: Muir
authors.forename: John F
authors.initials: JF
authors.lastname: Smyth
authors.forename: Hani
authors.initials: H
authors.lastname: Gabra
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005353:Fibronectins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D039422:Integrin alpha3 / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010088:Oxidoreductases / Q000235:genetics*; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000556:secondary; D011485:Protein Binding / Q000235:genetics; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000074584:WW Domain-Containing Oxidoreductase; D023041:Xenograft Model Antitumor Assays
chemical_list: D005353:Fibronectins; D039422:Integrin alpha3; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human