Bobak Parang1,2, Andrew M Kaz3,4, Caitlyn W Barrett1,2, Sarah P Short1,2, Wei Ning1,2, Cody E Keating1,2, Mukul K Mittal1,2, Rishi D Naik1, Mary K Washington5, Frank L Revetta5, J Joshua Smith6, Xi Chen7, Keith T Wilson1,2,8,9, Thomas Brand10, David M Bader11, William P Tansey8,11, Ru Chen4, Teresa A Brentnall4, William M Grady4,12, Christopher S Williams1,2,8,9. 1. Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA. 2. Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA. 3. Gastroenterology Section, VA Puget Sound Health Care System, Seattle, Washington, USA. 4. Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington, USA. 5. Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA. 6. Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 7. 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. 8. Vanderbilt Ingram Cancer Center, Nashville, Tennessee, USA. 9. Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee, USA. 10. Heart Science Centre, National Heart and Lung Institute, Imperial College of London, London, UK. 11. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA. 12. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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 humanpatients, 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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