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Carcinogenesis. 2019 Jan 23. doi: 10.1093/carcin/bgz007. [Epub ahead of print]

Blood vessel epicardial substance (BVES) reduces LRP6 receptor and cytoplasmic -catenin levels to modulate Wnt signaling and intestinal homeostasis.

Author information

1
Department of Medicine, Vanderbilt University Medical Center, London, U.K.
2
Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, New York, NY.
3
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, London, U.K.
4
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, London, U.K.
5
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
6
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
7
National Heart & Lung Institute, Imperial College London, London, U.K.
8
Veterans Affairs Tennessee Valley Health Care System, Nashville, TN, USA.

Abstract

Blood vessel epicardial substance (BVES, otherwise known as POPDC1) is an integral membrane protein known to regulate tight junction formation and epithelial-mesenchymal transition. BVES is underexpressed in a number of malignancies, including colorectal cancer. BVES loss leads to activation of the Wnt pathway, suggesting that decreased BVES expression functionally contributes to tumorigenesis. However, the mechanism by which BVES modulates Wnt signaling are unknown. Here we confirm that BVES loss increases -catenin protein levels, leads to Wnt pathway activation in a ligand-independent fashion, and coordinates with Wnt ligand to further increase Wnt signaling. We show that BVES loss increases levels and activation of the Wnt co-receptor, LRP6, in cell lines, murine adenoma tumoroids, and human-derived colonoids. We also demonstrate that BVES interacts with LRP6. Finally, murine tumor modelling using a Wnt-driven genetic model and a chemically-induced model of colorectal carcinogenesis demonstrates that BVES loss increases tumor multiplicity and dysplasia. Together, these results implicate BVES as an inhibitor of Wnt signaling, provide one of the first examples of a tight junction-associated protein regulating Wnt receptor levels, and expand the number of putative molecular targets for therapeutic intervention in colorectal cancer.

PMID:
30689807
DOI:
10.1093/carcin/bgz007

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