Aberrant expression, processing and degradation of dystroglycan in squamous cell carcinomas

Jie, Jing; Lien, Chun Fu; Sharma, Sanjay; Rice, J. R.; Brennan, Peter A.; Górecki, Dariusz C.

doi:10.1016/j.ejca.2004.05.018

Cited by 48 publications

(71 citation statements)

References 40 publications

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“…The presence of the 30 kDa b-DG fragment has been reported under different pathological conditions of the skeletal muscle, such as Duchenne muscular dystrophy, Fukuyama-type congenital dystrophy and sarcoglycanopathy (12). The 30 kDa b-DG fragment was also detected in tissues subjected to ischemic injury (13,14) and in joint tissues from patients affected by osteoarthritis (15); finally, b-DG degradation was also discovered in some forms of epithelial cancerous cells (16). In any case, the 30 kDa b-DG fragment lacks all or part of the b-DG ectodomain, as it can be detected using the monoclonal antibody 43DAG directed against the C-terminus of b-DG.…”

Section: Introductionmentioning

confidence: 82%

Enzymatic processing of β‐dystroglycan recombinant ectodomain by MMP‐9: Identification of the main cleavage site

et al. 2009

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SummaryDystroglycan (DG) is a membrane receptor belonging to the complex of glycoproteins associated to dystrophin. DG is formed by two subunits, a-DG, a highly glycosylated extracellular matrix protein, and b-DG, a transmembrane protein. The two DG subunits interact through the C-terminal domain of a-DG and the N-terminal extracellular domain of b-DG in a noncovalent way. Such interaction is crucial to maintain the integrity of the plasma membrane. In some pathological conditions, the interaction between the two DG subunits may be disrupted by the proteolytic activity of gelatinases (i.e. MMP-9 and/or MMP-2) that removes a portion or the whole b-DG ectodomain producing a 30 kDa truncated form of b-DG. However, the molecular mechanism underlying this event is still unknown. In this study, we carried out proteolysis of the recombinant extracellular domain of b-DG, b-DG(654-750) with human MMP-9, characterizing the catalytic parameters of its cleavage. Furthermore, using a combined approach based on SDS-PAGE, MALDI-TOF and HPLC-ESI-IT mass spectrometry, we were able to identify one main MMP-9 cleavage site that is localized between the amino acids His-715 and Leu-716 of b-DG, and we analysed the proteolytic fragments of b-DG(654-750) produced by MMP-9 enzymatic activity.

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Section: Introductionmentioning

confidence: 82%

Enzymatic processing of β‐dystroglycan recombinant ectodomain by MMP‐9: Identification of the main cleavage site

et al. 2009

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“…26,27 Indeed, as mentioned in the Introduction section, most of the information about DG in epithelial cells relate to its role in the process of tumor development and suggest that loss of DG expression is a frequent event in human epithelial cancers and might play an important role in tumor development by altering the interactions between cells and the surrounding matrix. 15,[17][18][19][20][21][22][25][26][27] The mechanisms responsible for the loss of aDG in tumor cells remain unknown and compelling evidence suggest that they might be different in different type of tumors but also amongst tumors of the same histogenetic origin 18,19,22 and in the same cells. 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.…”

Section: Discussionmentioning

confidence: 99%

“…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. 15,17,[19][20][21][22]25 Thus, loss of DG would inhibit the formation of strong contacts between ECM and the cytoskeleton of cells resulting, as for integrins, in less sticky tumor cells able to move unhindered in the extracellular matrix, thus predisposed to invade surrounding tissue and metastasize.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Sgambato

Camerini

Amoroso³

et al. 2007

Cancer Biology & Therapy

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The dystroglycan (DG) complex is a transmembrane glycoprotein that forms a continuous link from the extracellular matrix to the actin cytoskeleton. Deregulated expression of DG has been reported in a variety of human malignancies and related to tumor aggressiveness. In this study expression of the DG subunit was evaluated by immunostaining in a series of renal epithelial cancers and its relation with traditional prognostic indicators and with the clinical outcome of the patients was evaluated.aDG expression was undetectable in a significant fraction of tumors (54%). In renal cell carcinomas (RCC) loss of a-DG staining correlated with higher tumor grade (p = 0.02) but not with tumor stage nor tumor size. In clear cell RCC patients loss of aDG staining correlated with an increased risk of recurrence (p = 0.002 by log-rank test) and death (p = 0.004) also when patients with lower grade or stage tumors were analyzed separately. In a multivariate analysis loss of DG staining confirmed to be and independent predictor of shorter disease-free (p = 0.001; RR = 4.9) and overall (p = 0.009; RR = 4.9) survival stronger than tumor grade and size.These findings demonstrate that loss of aDG expression, which correspond to loss of a functional DG complex, is a frequent event in human renal tumorigenesis and is an independent predictor of early recurrence and death for patients with clear cell RCC.

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In silico bioinformatic tools for determining core genes from sets of genomes

Mahadevan

Seto

2010

Drug Development Research

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Objective Patients may be defined as nonadherent if they do not take their medications as prescribed by their physicians. Determinants of nonadherence may vary between and within patient groups. This study investigated the extent to which patients with systemic lupus erythematosus (SLE) show intentional and unintentional nonadherence, and the associations of nonadherence with psychological and medical parameters. Methods The study included 106 patients who were receiving at least one immunosuppressive agent to control their SLE. Level of self‐reported adherence and a measure of both intentional and unintentional nonadherence were obtained. Questionnaires were completed to assess associations between adherence and problems with cognitive functioning, beliefs about medicines, illness perceptions, emotional health, and disease characteristics. Results The mean self‐reported adherence rate for the total patient group was 86.7%. At least occasional intentional nonadherence was reported by 46.2% of patients and 58.5% of patients were at least occasionally unintentionally nonadherent. Problems with cognitive functioning, concerns about adverse effects of medication, and younger age were the strongest predictors of (non)adherence. Patients who were emotionally affected by their SLE were more likely to report low adherence, but this was not a significant predictor after accounting for other variables. Disease characteristics showed no relationship to measures of adherence. Conclusion Although SLE patients reported high levels of adherence on average, they commonly reported intentional and unintentional nonadherence. Adherence was associated with both cognitions and emotions. Nonadherence may be reduced by targeting emotional and cognitive functioning and by fine tuning doctor–patient communication to address patients' individual concerns about their medications.

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Aberrant expression, processing and degradation of dystroglycan in squamous cell carcinomas

Cited by 48 publications

References 40 publications

Enzymatic processing of β‐dystroglycan recombinant ectodomain by MMP‐9: Identification of the main cleavage site

Enzymatic processing of β‐dystroglycan recombinant ectodomain by MMP‐9: Identification of the main cleavage site

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

In silico bioinformatic tools for determining core genes from sets of genomes

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