Abstract
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.
Highlights
The C-terminal component, known as -dystroglycan, is embedded within the cell membrane, whereas the N-terminal component, ␣-dystroglycan, is present within the extracellular periphery but remains associated with -dystroglycan through non-covalent bonds. -Dystroglycan binds to actin [11], dystrophin [11], utrophin [11], and Grb2 [12] through its C-terminal intracellular domain. ␣-Dystroglycan, on the other hand, binds to extracellular matrix (ECM) proteins that contain laminin globular domains including laminins [13, 14], agrin [15], and perlecan [16], as well as to the transmembrane protein neurexin [17]. ␣-Dystroglycan is extensively decorated by three different types of glycan modifications: mucin type O-glycosylation, O-mannosylation, and N-glycosylation
We found that LARGE re- dependent on dystroglycan glycosylation status
These ␣-dystroglycan hypoglycosylated cells are not able to anchor to the basement membrane or organize ECM polymerization as effectively as normal epithelial cells, and their integration into the epithelium is compromised. These results demonstrate that LARGE is important for proper ␣-dystroglycan functional glycosylation and, thereby, for the ability of dystroglycan to function as an ECM protein receptor
Summary
Can is expressed in the metastatic cell lines MDA-MB-231, HeLa, H1299, and H2030, it is not functionally glycosylated. First studied the expression and glycosylation of ␣- and -dystroglycan in a series of model human cancer cell lines derived from breast, lung, and cervical tissue.
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