title: The non-canonical Wnt ligand, Wnt5a, is upregulated and associated with epithelial to mesenchymal transition in epithelial ovarian cancer.
abstract: OBJECTIVE
  Aberrant Wnt signalling has previously been associated with gynaecological cancers, and the aim of this study was to investigate the expression of Wnt5a in epithelial ovarian cancer, and clarify its role in activating or inhibiting β-catenin dependent and independent Wnt signalling pathways.
  
  
  METHODS
  Wnt5a expression was investigated in a large cohort of epithelial ovarian cancer patient samples using immunohistochemistry and correlated with clinicopathological variables. Wnt5a function was investigated in vitro in ovarian cell lines.
  
  
  RESULTS
  Wnt5a expression was found to be upregulated in all major subtypes (serous, endometrioid, clear cell and mucinous) of epithelial ovarian cancer compared to borderline tumours and benign controls. Treatment of ovarian surface epithelial cells with recombinant Wnt5a decreased cell adhesion and was associated with increased epithelial to mesenchymal transition (EMT). In addition, downstream targets of β-catenin dependent Wnt signalling were inhibited, and β-catenin independent targets increased following Wnt5a upregulation. Knockdown of Wnt5a in ovarian cancer cells was associated with a mesenchymal to epithelial transition (MET), but had no significant effect on cell migration or proliferation.
  
  
  CONCLUSIONS
  This study adds to the increasing evidence that Wnt signalling may play an important role in ovarian cancer development. Utilising an unparalleled large cohort of 623 patients, Wnt5a protein expression was shown to be significantly higher in ovarian cancer patients when compared to benign and borderline ovarian tumours and healthy control patients. In addition, we have utilised in vitro models to show for the first time in ovarian cancer that Wnt5a driven non-canonical pathways can alter epithelial to mesenchymal transition (EMT).
authors.affiliation: Wnt Signalling & Metastasis Group, Lowy Cancer Research Centre and Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Australia. Electronic address: caroline.ford@unsw.edu.au.
authors.forename: C E
authors.initials: CE
authors.lastname: Ford
authors.affiliation: Wnt Signalling & Metastasis Group, Lowy Cancer Research Centre and Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Punnia-Moorthy
authors.affiliation: Wnt Signalling & Metastasis Group, Lowy Cancer Research Centre and Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Australia.
authors.forename: C E
authors.initials: CE
authors.lastname: Henry
authors.affiliation: Wnt Signalling & Metastasis Group, Lowy Cancer Research Centre and Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Llamosas
authors.affiliation: Gynaecological Cancer Group, Lowy Cancer Research Centre and Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Nixdorf
authors.affiliation: School of Mathematics and Statistics, Faculty of Science, University of New South Wales, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Olivier
authors.affiliation: Department of Clinical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Caduff
authors.affiliation: Wnt Signalling & Metastasis Group, Lowy Cancer Research Centre and Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Australia.
authors.forename: R L
authors.initials: RL
authors.lastname: Ward
authors.affiliation: Gynaecological Cancer Group, Lowy Cancer Research Centre and Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Australia; Women's Hospital, University Hospital Basel, Basel, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Heinzelmann-Schwarz
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000209:etiology*; D010051:Ovarian Neoplasms / Q000209:etiology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051153:Wnt Proteins / Q000096:biosynthesis*; D000071818:Wnt-5a Protein
chemical_list: D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein
keywords: Epithelial ovarian cancer; Metastasis; Wnt signalling; Wnt5a; β-Catenin