Altered expression of alpha-dystroglycan subunit in human gliomas

Abstract

Dystroglycan (DG) is an integral membrane receptor of extracellular matrix proteins, composed of two subunits alpha and beta derived from a common precursor. In brain DG is expressed in neurons, glia limitans, astrocytic endfeet around vessels and endothelial cells. We investigate whether DG may play a role in brain tumors. Western blot and immunofluorescence analysis showed that, while beta-DG subunit was present, the highly glycosylated alpha-DG subunit was strongly reduced in surgically derived human glioblastoma biopsies, in low passage patient-derived cultures and in glioma cell lines, U87MG and A172MG, but not in all glioma cell lines tested. Immunohistochemistry of tumor frozen sections revealed that the loss of a-DG was confined in the tumor area but not around blood vessels. Overexpression of DG decreased the growth rate of the glioma cell lines lacking the highly glycosylated alpha-DG subunit and the colony-forming efficiency. Clonogenic assay in presence of temozolomide showed an additive effect between DG overexpression and drug treatment. Our data suggest that DG may be involved in the progression of primary brain tumors

Expression of dystroglycan correlates with tumor grade and predicts survival in renal cell carcinoma

“…25 DG overexpression was also shown to play a role in cytoskeletal organization, cell polarization and restriction of growth in response to BM proteins in epithelial cells 7,15 and to inhibit the growth of glioma cell lines. 23 These findings indicate that loss of DG expression is a frequent event in human malignancies and suggest that this molecule might play an important role in human tumor development. Although the mechanisms by which the DG complex regulates these cellular functions are not known, the available data indicate that loss of DG expression is a frequent event in human malignancies and suggest that this molecule might play an important role in human tumor development and progression.…”

“…However, evidence has grown for the importance of non-integrin receptors such as dystroglycan (DG), a ubiquitously expressed cell-surface receptor responsible for crucial interactions between ECM and the cytoplasmic compartment, whose expression has been shown to be reduced or lost in a variety of human cancer cell lines and primary tumors. 15,18,19,[21][22][23][24] DG is expressed in podocytes at the base of foot processes and DG-laminin interaction has been shown to be essential for epithelium development in kidney organ culture (Durbeej, 1995 #969). Moreover, it has been demonstrated that the DG complex undergoes changes in human glomerular diseases in which flattening of foot processes is directly associated with dissociation of laminin-DG complexes.…”

“…22 It is of interest that It is of interest that overexpression of an exogenous DG cDNA has been shown to be unable to restore a-DG detection in cancer cells that do not express it. 15,23,25 The current hypothesis is that specific post-transcriptional mechanisms, including a proteolytic cleavage as well as defects in the glycosylation or cell membrane localization, might be responsible for the lack of a functional DG complex in cancer cells. 18,19,21,22 Regardless of the underlying molecular mechanisms, loss of DG expression and/or function might play an important role in tumor development which has been mainly linked to its function as a cell surface receptor for components of the ECM.…”

“…7,15,16 We and others recently demonstrated that DG expression, and mainly aDG, is reduced or lost in a variety of human cancer cell lines and primary tumors. 15,[17][18][19][20][21][22][23][24] A reduction in the expression levels of DG was shown to be most pronounced in high-grade diseases 17,21 and to have a prognostic significance in breast cancer patients. 21 We also recently demonstrated that expression of an exogenous DG cDNA inhibits proliferation of both normal and cancer breast epithelial cells and reduces the anchorage-independent growth and tumorigenicity of breast cancer cells, thus confirming an important role of this molecule in the maintenance of the transformed phenotype of these cells.…”

Dystroglycan expression is reduced during prostate tumorigenesis and is regulated by androgens in prostate cancer cells

“…We and others recently demonstrated that DG expression, and mainly a-DG, is reduced or lost in a variety of human cancer cell lines and primary tumors, including prostate cancer (Losasso et al, 2000;Henry et al, 2001;Muschler et al, 2002;Sgambato et al, 2003Sgambato et al, , 2006bHerzog et al, 2004;Jing et al, 2004;Singh et al, 2004;Calogero et al, 2006). A reduction in the expression levels of DG was shown to be most pronounced in high-grade diseases Sgambato et al, 2003) and to have a prognostic significance in breast cancer patients (Sgambato et al, 2003).…”