# Modulation of junctional signaling by BVES in colorectal carcinoma > **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2020 · — ## Abstract Colorectal cancer (CRC) has a US incidence rate of almost 150,000 cases encompassing over 10% of new cancer diagnoses. In 2006 Within the Veterans Administration Healthcare System there were 4500 new cases and of those 650 were at advanced stage with very limited treatment options. Understanding the basic biology of underlying malignant transformation is critical in identifying new therapeutic targets and implementable strategies. Epithelial junctional pathology is common in malignancy. BVES is a tight junction associated protein which when suppressed induces mesenchymal transformation in human corneal epithelial cells. Further, we found decreased expression of BVES in CRC with reduced levels observed as early as adenomas indicating that its loss is an early event, likely implicating BVES in regulating additional pro- tumorigenic programs in addition to potentially contributing to metastasis. We determined the mechanism of underexpression was via transcriptional silencing via promoter hypermethylation and that this occurred in a large fraction of clinical samples, and virtually all CRC cell lines surveyed. We, and others now, have demonstrated that restoring BVES expression attenuated protumorigenic phenotypes in a variety of cancer cell lines. Collectively, this data suggests that BVES functions as a tumor suppressor in epithelial malignancy, thus BVES may represent a new diagnostic marker and/or therapeutic target in cancer. In the prior funding period, we determined that BVES was underexpressed in colitis associated carcinoma (CAC. We demonstrated the loss of BVES was functionally relevant as BVES deficient mice had increased tumor burden, and more severe dysplasia in inflammatory carcinogenesis modeling. Mechanistically, we determined that BVES interacts with and regulates the activities of PR61α:PP2A in regulating cellular c-Myc levels. Bves-/- intestine demonstrates increased stem cell markers and Bves-/- mice crossed with Lgr5-GFP reporter mice demonstrate increased Lgr5+ stem cell numbers. This is functionally relevant as Bves-/- intestine, cultured using 3D enteroid techniques, has increased plating efficiency, stem cell markers, and morphologically phenocopies ApcMin/+ tumors cultured in this system. Lastly, we have established techniques to culture, genetically modify, and establish as orthotopic xenografts, human CRC, thus developing a platform for testing whether BVES can modify the growth of established CRC and to determine the relative contribution of BVES regulated PP2A activity in the process. Much remains to be known about BVES function in epithelial malignancy. In this proposal we structure three specific aims designed to understand the role of BVES in tumor biology. First we will further our understanding of the BVES:PR61α:PP2A axis and determine whether BVES is a global regulator of PP2A activity. In the second we will use murine genetic approaches to test for BVES cooperation with Wnt in promoting tumorigenesis and determine... ## Key facts - **NIH application ID:** 9859299 - **Project number:** 5I01BX001426-08 - **Recipient organization:** VETERANS HEALTH ADMINISTRATION - **Principal Investigator:** Christopher S. Williams - **Activity code:** I01 (R01, R21, SBIR, etc.) - **Funding institute:** VA - **Fiscal year:** 2020 - **Award amount:** — - **Award type:** 5 - **Project period:** 2012-07-01 → 2020-12-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9859299 ## Citation > US National Institutes of Health, RePORTER application 9859299, Modulation of junctional signaling by BVES in colorectal carcinoma (5I01BX001426-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9859299. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*