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 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.
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.
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.
Pharmacology, Toxicology and Pharmaceutical Science
2
4%
Immunology and Microbiology
1
2%
Other
2
4%
Unknown
18
33%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 18. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 09 April 2017.
All research outputs
#1,829,769
of 23,577,654 outputs
Outputs from Gut
#1,108
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Outputs of similar age
#33,299
of 399,006 outputs
Outputs of similar age from Gut
#18
of 78 outputs
Altmetric has tracked 23,577,654 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 92nd percentile: it's in the top 10% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 6,956 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 19.0. This one has done well, scoring higher than 83% of its peers.
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We're also able to compare this research output to 78 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 76% of its contemporaries.
