Control of glioma cell migration and invasiveness by GDF-15

Abstract

// Paula Codó 1 , Michael Weller 1 , Kerstin Kaulich 2 , Daniel Schraivogel 3 , Manuela Silginer 1 , Guido Reifenberger 2 , Gunter Meister 3 , Patrick Roth 1 1 Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland 2 Department of Neuropathology, Heinrich Heine University, Düsseldorf, and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany 3 Department of Biochemistry I, University of Regensburg, Regensburg, Germany Correspondence to: Patrick Roth, e-mail: patrick.roth@usz.ch Keywords: GDF-15, glioblastoma, invasion, TCGA, serpine1 Received: June 28, 2015      Accepted: November 15, 2015      Published: January 04, 2016 ABSTRACT Growth and differentiation factor (GDF)-15 is a member of the transforming growth factor (TGF)-β family of proteins. GDF-15 levels are increased in the blood and cerebrospinal fluid of glioblastoma patients. Using a TCGA database interrogation, we demonstrate that high GDF-15 expression levels are associated with poor survival of glioblastoma patients. To elucidate the role of GDF-15 in glioblastoma in detail, we confirmed that glioma cells express GDF-15 mRNA and protein in vitro . To allow for a detailed functional characterization, GDF-15 expression was silenced using RNA interference in LNT-229 and LN-308 glioma cells. Depletion of GDF-15 had no effect on cell viability. In contrast, GDF-15-deficient cells displayed reduced migration and invasion, in the absence of changes in Smad2 or Smad1/5/8 phosphorylation. Conversely, exogenous GDF-15 stimulated migration and invasiveness. Large-scale expression profiling revealed that GDF-15 gene silencing resulted in minor changes in the miRNA profile whereas several genes, including members of the plasminogen activator/inhibitor complex, were deregulated at the mRNA level. One of the newly identified genes induced by GDF-15 gene silencing was the serpin peptidase inhibitor, clade E nexin group 1 ( serpine1 ) which is induced by TGF-β and known to inhibit migration and invasiveness. However, serpine1 down-regulation alone did not mediate GDF-15-induced promotion of migration and invasiveness. Our findings highlight the complex contributions of GDF-15 to the invasive phenotype of glioma cells and suggest anti-GDF-15 approaches as a promising therapeutic strategy.