title: BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis.
abstract: Blood vessel epicardial substance (BVES) is a tight junction-associated protein that regulates epithelial-mesenchymal states and is underexpressed in epithelial malignancy. However, the functional impact of BVES loss on tumourigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function and its relevance to patients with IBD.
  
  
  
  We determinedBVESpromoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measuredBVESmRNA levels in a tissue microarray consisting of normal colons and CAC samples.Bves-/-and wild-type mice (controls) were administered azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce tumour formation. Last, we used a yeast two-hybrid screen to identify BVES interactors and performed mechanistic studies in multiple cell lines to define how BVES reduces c-Myc levels.
  
  
  
  BVESmRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly,BVESpromoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients,Bveswas underexpressed in experimental inflammatory carcinogenesis, andBves-/-mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis ofBves-/-tumours revealed Wnt activation and increased c-Myc levels. Mechanistically, we identified a new signalling pathway whereby BVES interacts with PR61α, a protein phosphatase 2A regulatory subunit, to mediate c-Myc destruction.
  
  
  
  Loss of BVES promotes inflammatory tumourigenesis through dysregulation of Wnt signalling and the oncogene c-Myc.BVESpromoter methylation status may serve as a CAC biomarker.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Bobak
authors.initials: B
authors.lastname: Parang
authors.affiliation: Gastroenterology Section, VA Puget Sound Health Care System, Seattle, Washington, USA.|Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Kaz
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Caitlyn W
authors.initials: CW
authors.lastname: Barrett
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Sarah P
authors.initials: SP
authors.lastname: Short
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Ning
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Cody E
authors.initials: CE
authors.lastname: Keating
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Mukul K
authors.initials: MK
authors.lastname: Mittal
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Rishi D
authors.initials: RD
authors.lastname: Naik
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Washington
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Frank L
authors.initials: FL
authors.lastname: Revetta
authors.affiliation: Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: J Joshua
authors.initials: JJ
authors.lastname: Smith
authors.affiliation: Division of Biostatistics, Department of Public Health Sciences, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.|Vanderbilt Ingram Cancer Center, Nashville, Tennessee, USA.|Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee, USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
authors.affiliation: Heart Science Centre, National Heart and Lung Institute, Imperial College of London, London, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brand
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Bader
authors.affiliation: Vanderbilt Ingram Cancer Center, Nashville, Tennessee, USA.|Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Tansey
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Ru
authors.initials: R
authors.lastname: Chen
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Brentnall
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington, USA.|Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Grady
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.|Vanderbilt Ingram Cancer Center, Nashville, Tennessee, USA.|Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Williams
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D018938:Caco-2 Cells; D063646:Carcinogenesis / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism*; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019175:DNA Methylation; D016264:Dextran Sulfate; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D054648:Protein Phosphatase 2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D016264:Dextran Sulfate; D008565:Membrane Proteins; D009124:Muscle Proteins; D054648:Protein Phosphatase 2; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C530749:POPDC1 protein, human; C498789:Bves protein, mouse; C551901:Ppp2r5a protein, mouse
keywords: CANCER; COLONIC NEOPLASMS; COLORECTAL CANCER; IBD; ULCERATIVE COLITIS