Control of glioma cell migration and invasiveness by GDF-15
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Paula Codó1, Michael Weller1, Kerstin Kaulich2, Daniel Schraivogel3, Manuela Silginer1, Guido Reifenberger2, Gunter Meister3, Patrick Roth1
1Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
2Department of Neuropathology, Heinrich Heine University, Düsseldorf, and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
3Department of Biochemistry I, University of Regensburg, Regensburg, Germany
Patrick Roth, e-mail: [email protected]
Keywords: GDF-15, glioblastoma, invasion, TCGA, serpine1
Received: June 28, 2015 Accepted: November 15, 2015 Published: January 04, 2016
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.
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