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

Abstract

// Qiu Yushi 1, * , Zhimin Li 1, * , Christina A. Von Roemeling 2, * , Heike Doeppler 1 , Laura A. Marlow 1 , Betty Y.S. Kim 3 , Derek C. Radisky 1 , Peter Storz 1 , John A. Copland 1 , Han W. Tun 1, 4 1 Department of Cancer Biology, Jacksonville, Florida, USA 2 Mayo Graduate School, Mayo Clinic, Rochester, Minnesota, USA 3 Department of Neurosurgery, Mayo Clinic, Jacksonville, Florida, USA 4 Department of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida, USA * These authors contributed equally to this work Correspondence to: Han W. Tun, email: tun.han@mayo.edu Keywords: osteopontin (OPN), CNS lymphoma, proliferation, invasion, NF-κB signaling Received: February 01, 2016      Accepted: March 04, 2016      Published: April 01, 2016 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.