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.
Highlights
Glioblastoma is an aggressive malignancy of the brain characterized by highly infiltrative and rapid growth
When the median was used as cut-off, glioblastoma patients with tumors displaying lower Growth and differentiation factor (GDF)-15 expression had longer overall survival than patients with tumors characterized by GDF-15 expression higher than the median (p = 0.017) (Fig. 1A)
The overall survival probability was significantly higher for patients of group G4, which is characterized by the lowest GDF-15 levels (Fig. 1D), corroborating the hypothesis that GDF-15 contributes to the malignant phenotype of glioblastoma
Summary
Glioblastoma is an aggressive malignancy of the brain characterized by highly infiltrative and rapid growth. Transforming growth factor (TGF)-β is a major player in the promotion of glioblastoma growth and is the master cytokine within the TGF-β superfamily. We have previously shown that another member of this family, growth and differentiation factor (GDF)-15, known as macrophage inhibitory cytokine (MIC)-1, contributes to the immune escape of gliomas, a hallmark of these tumors [2]. GDF-15 is synthetized as an inactive proprotein precursor that is processed by cleavage, folding and dimerization [3] and subsequently secreted. It may act in a paracrine manner on various cells within the tumor microenvironment [4]. Unprocessed, secreted precursor molecules bind components of the extracellular matrix, thereby creating latent stromal GDF-15 storages [5]
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