Blood vessel epicardial substance (BVES) and BVES binding partners in intestinal homeostasis and tumorigenesis
Thompson, Joshua James
Blood vessel epicardial substance (BVES or POPDC1) is a tight junction-associated adhesion molecule that regulates epithelial-mesenchymal transition and is downregulated in colorectal cancer via promoter hypermethylation, suggesting that BVES may function as a tumor suppressor. Accordingly, BVES loss is associated with hyperactivation of the Wnt pathway, a key initiator and driver of colorectal cancer; however, the mechanism by which BVES regulates Wnt signaling is unknown. Here, using a combination of reporter assays, cell lines, three dimensional organoid cultures, and murine genetic models of intestinal tumorigenesis, we show that BVES interacts with the Wnt co-receptor LRP6, and that BVES loss increases LRP6 receptor levels and activation. Loss of BVES also increased tumor multiplicity and dysplasia in two separate mouse models of colon tumorigenesis. Together, these results implicate BVES in the regulation of Wnt signaling through modulating LRP6 receptor levels and confirm its role as a tumor suppressor by inhibiting Wnt ligand-independent signaling cascades. Additionally, to expand the known roles for BVES within the cell, our lab had previously performed a yeast-two-hybrid screen to identify novel BVES interacting proteins which identified Breast cancer anti-estrogen resistance 3 (BCAR3). We identified a previously uncharacterized role for BCAR3 in intestinal tumorigenesis. BCAR3 mediates colorectal cancer cell migration and proliferation and is downregulated in human colorectal cancer.