title: Osteopontin is a multi-faceted pro-tumorigenic driver for central nervous system lymphoma.
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.
authors.affiliation: Department of Cancer Biology, Jacksonville, Florida, USA.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Yushi
authors.affiliation: Department of Cancer Biology, Jacksonville, Florida, USA.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Li
authors.affiliation: Mayo Graduate School, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Von Roemeling
authors.affiliation: Department of Cancer Biology, Jacksonville, Florida, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Doeppler
authors.affiliation: Department of Cancer Biology, Jacksonville, Florida, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Marlow
authors.affiliation: Department of Neurosurgery, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Betty Y S
authors.initials: BY
authors.lastname: Kim
authors.affiliation: Department of Cancer Biology, Jacksonville, Florida, USA.
authors.forename: Derek C
authors.initials: DC
authors.lastname: Radisky
authors.affiliation: Department of Cancer Biology, Jacksonville, Florida, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Storz
authors.affiliation: Department of Cancer Biology, Jacksonville, Florida, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Copland
authors.affiliation: Department of Cancer Biology, Jacksonville, Florida, USA.|Department of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Han W
authors.initials: HW
authors.lastname: Tun
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D016543:Central Nervous System Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020784:Matrix Metalloproteinase 8 / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D047368:Tumor Burden; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D016328:NF-kappa B; C506895:SPP1 protein, human; C117046:TNIP1 protein, human; D053495:Osteopontin; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; C488762:MMP8 protein, human; D020784:Matrix Metalloproteinase 8
keywords: CNS lymphoma; NF-κB signaling; invasion; osteopontin (OPN); proliferation