BVES regulates EMT in human corneal and colon cancer cells and is silenced via promoter methylation in human colorectal carcinoma
Open Access
- 3 October 2011
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 121 (10), 4056-4069
- https://doi.org/10.1172/jci44228
Abstract
The acquisition of a mesenchymal phenotype is a critical step in the metastatic progression of epithelial carcinomas. Adherens junctions (AJs) are required for suppressing this epithelial-mesenchymal transition (EMT) but less is known about the role of tight junctions (TJs) in this process. Here, we investigated the functions of blood vessel epicardial substance (BVES, also known as POPDC1 and POP1), an integral membrane protein that regulates TJ formation. BVES was found to be underexpressed in all stages of human colorectal carcinoma (CRC) and in adenomatous polyps, indicating its suppression occurs early in transformation. Similarly, the majority of CRC cell lines tested exhibited decreased BVES expression and promoter DNA hypermethylation, a modification associated with transcriptional silencing. Treatment with a DNA-demethylating agent restored BVES expression in CRC cell lines, indicating that methylation represses BVES expression. Reexpression of BVES in CRC cell lines promoted an epithelial phenotype, featuring decreased proliferation, migration, invasion, and anchorage-independent growth; impaired growth of an orthotopic xenograft; and blocked metastasis. Conversely, interfering with BVES function by expressing a dominant-negative mutant in human corneal epithelial cells induced mesenchymal features. These biological outcomes were associated with changes in AJ and TJ composition and related signaling. Therefore, BVES prevents EMT, and its epigenetic silencing may be an important step in promoting EMT programs during colon carcinogenesis.This publication has 54 references indexed in Scilit:
- Experimentally Derived Metastasis Gene Expression Profile Predicts Recurrence and Death in Patients With Colon CancerGastroenterology, 2010
- Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomasJCI Insight, 2010
- Epithelial-Mesenchymal Transitions in Development and DiseaseCell, 2009
- The basics of epithelial-mesenchymal transitionJCI Insight, 2009
- EMT: When epithelial cells decide to become mesenchymal-like cellsJCI Insight, 2009
- Identification of a Novel Intracellular Interaction Domain Essential for Bves FunctionPLOS ONE, 2008
- DNA Methylation in Tumor and Matched Normal Tissues from Non-Small Cell Lung Cancer PatientsCancer Epidemiology, Biomarkers & Prevention, 2008
- The transcription factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarityOncogene, 2007
- Comprehensive analysis of CpG islands in human chromosomes 21 and 22Proceedings of the National Academy of Sciences of the United States of America, 2002
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001