Loss of α-Dystroglycan Laminin Binding in Epithelium-derived Cancers Is Caused by Silencing of LARGE

The interaction between epithelial cells and the extracellular matrix is crucial for tissue architecture and function and is compromised during cancer progression. Dystroglycan is a membrane receptor that mediates interactions between cells and basement membranes in various epithelia. In many epithe...

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Bibliographic Details
Published in:The Journal of biological chemistry 2009-04, Vol.284 (17), p.11279-11284
Main Authors: de Bernabé, Daniel Beltrán-Valero, Inamori, Kei-ichiro, Yoshida-Moriguchi, Takako, Weydert, Christine J., Harper, Hollie A., Willer, Tobias, Henry, Michael D., Campbell, Kevin P.
Format: Article
Language:English
Subjects:
Cell Adhesion
Cell Line, Tumor
Dystroglycans - metabolism
Epithelium - pathology
Gene Expression Regulation, Neoplastic
Gene Silencing
Glycosylation
HeLa Cells
Humans
Laminin - metabolism
Models, Biological
N-Acetylglucosaminyltransferases - metabolism
Neoplasm Metastasis
Protein Binding
Skin Neoplasms - metabolism
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Summary:The interaction between epithelial cells and the extracellular matrix is crucial for tissue architecture and function and is compromised during cancer progression. Dystroglycan is a membrane receptor that mediates interactions between cells and basement membranes in various epithelia. In many epithelium-derived cancers, β-dystroglycan is expressed, but α-dystroglycan is not detected. Here we report that α-dystroglycan is correctly expressed and trafficked to the cell membrane but lacks laminin binding as a result of the silencing of the like-acetylglucosaminyltransferase (LARGE) gene in a cohort of highly metastatic epithelial cell lines derived from breast, cervical, and lung cancers. Exogenous expression of LARGE in these cancer cells restores the normal glycosylation and laminin binding of α-dystroglycan, leading to enhanced cell adhesion and reduced cell migration in vitro. Our findings demonstrate that LARGE repression is responsible for the defects in dystroglycan-mediated cell adhesion that are observed in epithelium-derived cancer cells and point to a defect of dystroglycan glycosylation as a factor in cancer progression.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.C900007200