Abstract
Osteopontin (OPN) is the most upregulated gene in primary central nervous system lymphoma (PCNSL) compared to non-CNS diffuse large B cell lymphoma (DLBCL). We show here that OPN is a key mediator of intracerebral tumor growth, invasion, and dissemination in CNS lymphoma, and that these effects depend upon activation of NF-κB. We further show that activation of NF-κB by OPN occurs through a unique mechanism in which intracellular OPN (iOPN) causes transcriptional downregulation of the NF-κB inhibitors, A20/TNFAIP3 and ABIN1/TNIP1, and secretory OPN (sOPN) promotes receptor-mediated activation of NF-κB. We also identify NF-κB-mediated induction of matrix metalloproteinase-8 (MMP-8) as a specific feature of OPN-mediated tissue invasion. These results implicate OPN as a candidate for development of targeted therapy for patients with PCNSL.
Keywords:
CNS lymphoma; NF-κB signaling; invasion; osteopontin (OPN); proliferation.
MeSH terms
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Animals
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Autocrine Communication
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Cell Line, Tumor
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Cell Movement*
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Cell Proliferation*
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Central Nervous System Neoplasms / genetics
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Central Nervous System Neoplasms / metabolism*
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Central Nervous System Neoplasms / pathology
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Gene Expression Regulation, Neoplastic
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Humans
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Lymphoma, B-Cell / genetics
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Lymphoma, B-Cell / metabolism*
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Lymphoma, B-Cell / pathology
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Matrix Metalloproteinase 8 / genetics
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Matrix Metalloproteinase 8 / metabolism
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Mice, Nude
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Neoplasm Invasiveness
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Neoplasm Metastasis
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Osteopontin / genetics
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Osteopontin / metabolism*
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RNA Interference
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Signal Transduction
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Time Factors
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Transcription, Genetic
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Transfection
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Tumor Burden
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Tumor Necrosis Factor alpha-Induced Protein 3 / genetics
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Tumor Necrosis Factor alpha-Induced Protein 3 / metabolism
Substances
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DNA-Binding Proteins
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NF-kappa B
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SPP1 protein, human
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TNIP1 protein, human
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Osteopontin
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TNFAIP3 protein, human
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Tumor Necrosis Factor alpha-Induced Protein 3
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MMP8 protein, human
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Matrix Metalloproteinase 8