Abstract
Uncontrolled growth and diffused invasion are major causes of mortality in patients with malignant gliomas. Nodal has been shown to have a central role in the tumorigenic signaling pathways of malignant melanoma. In this study, we show that grade IV human glioma cell lines expressed different levels of Nodal, paralleled to the potential for cell invasiveness. Treatment of glioma cell lines with recombinant Nodal (rNodal) increased matrix metalloproteinase 2 (MMP-2) secretion and cell invasiveness. The ectopic expression of Nodal in GBM glioma cells that expressed Nodal at low level resulted in increased MMP-2 secretion, enhanced cell invasiveness, raised cell proliferation rates in vitro, increased tumor growth in vivo, and was associated with poor survival in a mice xenograft model. In contrast, the knockdown of Nodal expression in U87MG glioma cells with high Nodal expression level had reduced MMP-2 secretion, less cell invasiveness, lower tumor growth in vivo and longer lifespan in mice with U87MG/shNodal cell xenografts. In addition, Nodal knockdown promoted the reversion of malignant glioma cells toward a differentiated astrocytic phenotype. Furthermore, our data support the notion that Nodal may regulate glioma progression through the induction of the leukemia inhibitory factor (LIF) and Cripto-1 through activated Smad.
MeSH terms
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Animals
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Cell Division
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Cell Line, Tumor
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Central Nervous System Neoplasms / enzymology
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Central Nervous System Neoplasms / genetics
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Central Nervous System Neoplasms / pathology
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Disease Progression
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Epidermal Growth Factor / biosynthesis
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GPI-Linked Proteins
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Gene Expression Regulation, Neoplastic
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Gene Knockout Techniques
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Glioma / enzymology
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Glioma / genetics
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Glioma / pathology*
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Humans
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Intercellular Signaling Peptides and Proteins
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Intracellular Signaling Peptides and Proteins / genetics*
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Intracellular Signaling Peptides and Proteins / metabolism
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Intracellular Signaling Peptides and Proteins / pharmacology
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Leukemia Inhibitory Factor / genetics
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Matrix Metalloproteinase 2 / genetics
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Matrix Metalloproteinase 2 / metabolism
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Membrane Glycoproteins / biosynthesis
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism
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Membrane Proteins / pharmacology
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Mice
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Neoplasm Invasiveness
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Neoplasm Proteins / biosynthesis
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Recombinant Proteins / therapeutic use
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Smad Proteins / metabolism
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Tissue Inhibitor of Metalloproteinase-2 / metabolism
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Transfection
Substances
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GPI-Linked Proteins
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Intercellular Signaling Peptides and Proteins
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Intracellular Signaling Peptides and Proteins
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LIF protein, human
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Leukemia Inhibitory Factor
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Membrane Glycoproteins
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Membrane Proteins
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NOMO3 protein, human
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Neoplasm Proteins
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Recombinant Proteins
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Smad Proteins
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TDGF1 protein, human
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Tissue Inhibitor of Metalloproteinase-2
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Epidermal Growth Factor
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Matrix Metalloproteinase 2