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Original article
BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis
  1. Bobak Parang1,2,
  2. Andrew M Kaz3,4,
  3. Caitlyn W Barrett1,2,
  4. Sarah P Short1,2,
  5. Wei Ning1,2,
  6. Cody E Keating1,2,
  7. Mukul K Mittal1,2,
  8. Rishi D Naik1,
  9. Mary K Washington5,
  10. Frank L Revetta5,
  11. J Joshua Smith6,
  12. Xi Chen7,
  13. Keith T Wilson1,2,8,9,
  14. Thomas Brand10,
  15. David M Bader11,
  16. William P Tansey8,11,
  17. Ru Chen4,
  18. Teresa A Brentnall4,
  19. William M Grady4,12,
  20. Christopher S Williams1,2,8,9
  1. 1Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA
  2. 2Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA
  3. 3Gastroenterology Section, VA Puget Sound Health Care System, Seattle, Washington, USA
  4. 4Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington, USA
  5. 5Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA
  6. 6Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  7. 7Division 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
  8. 8Vanderbilt Ingram Cancer Center, Nashville, Tennessee, USA
  9. 9Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee, USA
  10. 10Heart Science Centre, National Heart and Lung Institute, Imperial College of London, London, UK
  11. 11Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA
  12. 12Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  1. Correspondence to Dr Christopher S Williams, Associate Professor of Medicine and Cancer Biology, Director, Physician Scientist Training Programme, Staff Physician, VA Health System, Vanderbilt University School of Medicine, 1065D MRB-IV, B2215 Garland Ave, Nashville, Tennessee 37232, USA; christopher.williams{at}vanderbilt.edu

Abstract

Objective 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.

Design We determined BVES promoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measured BVES mRNA 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.

Results BVES mRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly, BVES promoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients, Bves was underexpressed in experimental inflammatory carcinogenesis, and Bves−/− mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of Bves−/− 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.

Conclusion Loss of BVES promotes inflammatory tumourigenesis through dysregulation of Wnt signalling and the oncogene c-Myc. BVES promoter methylation status may serve as a CAC biomarker.

  • CANCER
  • IBD
  • ULCERATIVE COLITIS
  • COLONIC NEOPLASMS
  • COLORECTAL CANCER

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