Keith Wilson
Faculty Member
Last active: 8/13/2019

BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis.

Parang B, Kaz AM, Barrett CW, Short SP, Ning W, Keating CE, Mittal MK, Naik RD, Washington MK, Revetta FL, Smith JJ, Chen X, Wilson KT, Brand T, Bader DM, Tansey WP, Chen R, Brentnall TA, Grady WM, Williams CS
Gut. 2017 66 (5): 852-862

PMID: 28389570 · PMCID: PMC5385850 · DOI:10.1136/gutjnl-2015-310255

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 promoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measured mRNA levels in a tissue microarray consisting of normal colons and CAC samples. 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 - mRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly, promoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients, was underexpressed in experimental inflammatory carcinogenesis, and mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of 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. promoter methylation status may serve as a CAC biomarker.

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MeSH Terms (26)

Animals Biomarkers, Tumor Caco-2 Cells Carcinogenesis Cell Adhesion Molecules Colitis Colitis, Ulcerative Colon Colonic Neoplasms Dextran Sulfate DNA Methylation Down-Regulation Female Gene Expression Profiling HEK293 Cells Humans Male Membrane Proteins Mice Mice, Knockout Muscle Proteins Promoter Regions, Genetic Protein Phosphatase 2 Proto-Oncogene Proteins c-myc RNA, Messenger Wnt Signaling Pathway

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