Journal article
BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis
Gut, Vol.66(5), pp.852-862
05/01/2017
DOI: 10.1136/gutjnl-2015-310255
PMCID: PMC5385850
PMID: 28389570
Abstract
ObjectiveBlood 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.DesignWe 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.ResultsBVES 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.ConclusionLoss 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.
Details
- Title: Subtitle
- BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis
- Creators
- Bobak Parang - Vanderbilt UniversityAndrew M Kaz - VA Puget Sound Health Care SystemCaitlyn W Barrett - Vanderbilt UniversitySarah P Short - Vanderbilt UniversityWei Ning - Vanderbilt UniversityCody E Keating - Vanderbilt UniversityMukul K Mittal - Vanderbilt UniversityRishi D Naik - Vanderbilt UniversityMary K Washington - Vanderbilt UniversityFrank L Revetta - Vanderbilt UniversityJ Joshua Smith - Memorial Sloan Kettering Cancer CenterXi Chen - University of MiamiKeith T Wilson - Vanderbilt UniversityThomas Brand - Imperial College LondonDavid M Bader - Vanderbilt UniversityWilliam P Tansey - Vanderbilt UniversityRu Chen - University of WashingtonTeresa A Brentnall - University of WashingtonWilliam M Grady - University of WashingtonChristopher S Williams - Vanderbilt Health
- Resource Type
- Journal article
- Publication Details
- Gut, Vol.66(5), pp.852-862
- DOI
- 10.1136/gutjnl-2015-310255
- PMID
- 28389570
- PMCID
- PMC5385850
- NLM abbreviation
- Gut
- ISSN
- 0017-5749
- eISSN
- 1468-3288
- Language
- English
- Date published
- 05/01/2017
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984420839802771
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