title: VEPH1 expression decreases vascularisation in ovarian cancer xenografts and inhibits VEGFA and IL8 expression through inhibition of AKT activation.
abstract: BACKGROUND
  VEPH1 is amplified in several cancers including ovarian but its impact on tumour progression is unknown. Previous work has shown that VEPH1 inhibits TGFβ signalling while its Drosophila ortholog increases tissue growth, raising the possibility that VEPH1 could impact tumour growth or progression.
  
  
  METHODS
  A CRISPR approach was used to disrupt VEPH1 expression in ovarian cancer ES-2 cells, while VEPH1-negative SKOV3 cells were stably transfected with VEPH1 cDNA. The impact of altered VEPH1 expression was assessed using in vitro and in vivo assays and mechanistic studies were performed in vitro.
  
  
  RESULTS
  VEPH1 expression in SKOV3 cells resulted in a reduced tumour growth rate associated with increased necrotic area, and decreased microvessel density and VEGF-A levels relative to tumours formed by mock-transfected cells. VEPH1 expression also decreased VEGFA and IL8 expression in SKOV3 cells and was associated with decreased activated AKT levels. These effects were not observed in ES-2 cells, which bear a BRAFV600Eactivating mutation that leads to constitutively increased IL8 and VEGFA expression.
  
  
  CONCLUSIONS
  VEPH1 expression in SKOV3 ovarian cancer cells inhibits AKT activation to decrease VEGFA and IL8 expression, which leads to decreased tumour vascularisation and progression.
authors.affiliation: Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, 60 Murray Street, Toronto, M5T 3L9 ON, Canada.|Department of Obstetrics and Gynecology, University of Toronto, 123 Edward Street, Toronto, M5G 1E2 ON, Canada.
authors.forename: Premalatha
authors.initials: P
authors.lastname: Shathasivam
authors.affiliation: Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, 60 Murray Street, Toronto, M5T 3L9 ON, Canada.|Department of Obstetrics and Gynecology, University of Toronto, 123 Edward Street, Toronto, M5G 1E2 ON, Canada.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kollara
authors.affiliation: Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, 60 Murray Street, Toronto, M5T 3L9 ON, Canada.|Department of Obstetrics and Gynecology, University of Toronto, 123 Edward Street, Toronto, M5G 1E2 ON, Canada.|Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, M5S 1A8 ON, Canada.
authors.forename: Thomasina
authors.initials: T
authors.lastname: Spybey
authors.affiliation: Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, 60 Murray Street, Toronto, M5T 3L9 ON, Canada.
authors.forename: Soyeon
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Laboratory Medicine, University Health Network, 190 Elizabeth Street, Toronto, M5G 2C4 ON, Canada.
authors.forename: Blaise
authors.initials: B
authors.lastname: Clarke
authors.affiliation: Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, M5S 3G5 ON, Canada.
authors.forename: Maurice J
authors.initials: MJ
authors.lastname: Ringuette
authors.affiliation: Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, 60 Murray Street, Toronto, M5T 3L9 ON, Canada.|Department of Obstetrics and Gynecology, University of Toronto, 123 Edward Street, Toronto, M5G 1E2 ON, Canada.|Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, M5S 1A8 ON, Canada.
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Brown
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C467484:VEGFA protein, human; C000619871:VEPH1 protein, human; D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt