Osteopontin is a multi-faceted pro-tumorigenic driver for central nervous system lymphoma

Oncotarget. 2016 May 31;7(22):32156-71. doi: 10.18632/oncotarget.8537.

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

  • Animals
  • Autocrine Communication
  • Cell Line, Tumor
  • Cell Movement*
  • Cell Proliferation*
  • Central Nervous System Neoplasms / genetics
  • Central Nervous System Neoplasms / metabolism*
  • Central Nervous System Neoplasms / pathology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lymphoma, B-Cell / genetics
  • Lymphoma, B-Cell / metabolism*
  • Lymphoma, B-Cell / pathology
  • Matrix Metalloproteinase 8 / genetics
  • Matrix Metalloproteinase 8 / metabolism
  • Mice, Nude
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Osteopontin / genetics
  • Osteopontin / metabolism*
  • RNA Interference
  • Signal Transduction
  • Time Factors
  • Transcription, Genetic
  • Transfection
  • Tumor Burden
  • Tumor Necrosis Factor alpha-Induced Protein 3 / genetics
  • Tumor Necrosis Factor alpha-Induced Protein 3 / metabolism

Substances

  • DNA-Binding Proteins
  • NF-kappa B
  • SPP1 protein, human
  • TNIP1 protein, human
  • Osteopontin
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • MMP8 protein, human
  • Matrix Metalloproteinase 8