Journal article
Blood vessel epicardial substance reduces LRP6 receptor and cytoplasmic beta-catenin levels to modulate Wnt signaling and intestinal homeostasis
Carcinogenesis (New York), Vol.40(9), pp.1086-1098
09/01/2019
DOI: 10.1093/carcin/bgz007
PMCID: PMC8067673
PMID: 30689807
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 is unknown. Here, we confirm that BVES loss increases beta-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 modeling using a Wnt-driven genetic model and a chemically induced model of colorectal carcinogenesis demonstrate 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.
Details
- Title: Subtitle
- Blood vessel epicardial substance reduces LRP6 receptor and cytoplasmic beta-catenin levels to modulate Wnt signaling and intestinal homeostasis
- Creators
- Joshua J. Thompson - Vanderbilt University Medical CenterSarah P. Short - Vanderbilt University Medical CenterBobak Parang - Vanderbilt University Medical CenterRachel E. Brown - Vanderbilt University Medical CenterChenxuan Li - Vanderbilt UniversityVictoria H. Ng - Vanderbilt UniversityKenyi Saito-Diaz - Vanderbilt UniversityYash A. Choksi - Vanderbilt UniversityMary K. Washington - Vanderbilt UniversityJesse Joshua Smith - Memorial Sloan Kettering Cancer CenterBarbara Fingleton - Vanderbilt UniversityThomas Brand - Imperial College LondonEthan Lee - Vanderbilt UniversityRobert J. Coffey - Vanderbilt UniversityChristopher S. Williams - Vanderbilt University Medical Center
- Resource Type
- Journal article
- Publication Details
- Carcinogenesis (New York), Vol.40(9), pp.1086-1098
- Publisher
- Oxford Univ Press
- DOI
- 10.1093/carcin/bgz007
- PMID
- 30689807
- PMCID
- PMC8067673
- ISSN
- 0143-3334
- eISSN
- 1460-2180
- Number of pages
- 13
- Grant note
- 1I01BX001426 / Office of Medical Research, Department of Veterans Affairs; US Department of Veterans Affairs R01DK099204; R35CA197570; P50CA95103; R35GM122516; P50CA095103; T32GM007347; F30DK111107; F30DK096718; F32DK108492; F30DK120149; P30DK058404; UL1TR000445 / National Institute of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 09/01/2019
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984420844402771
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