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 twohybrid
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.