Growth differentiation factor-15 overexpression promotes cell proliferation and predicts poor prognosis in cerebral lower-grade gliomas correlated with hypoxia and glycolysis signature

Aims: Growth differentiation factor-15 (GDF15) plays complex and controversial roles in cancer. In this study, the prognostic value and the exact biological function of GDF15 in cerebral lower-grade gliomas (LGGs) and its potential molecular targets were examined.Main methods: Wilcoxon signed-rank test and logistic regression were applied to analyze associations between GDF15 expression and clinical characteristics using the Cancer Genome Atlas (TCGA) database. Overall survival was analyzed using Kaplan-Meier and Cox analyses. Gene set enrichment analysis (GSEA) and the hypoxia risk model was conducted to identify the potential molecular mechanisms underlying the effects of GDF15 on LGGs tumorigenesis. The biological function of GDF15 was examined using gain-and loss-of-function experiments, and a recombinant hGDF15 protein in LGG SW1783 cells in vitro.Key findings: We found that higher GDF15 expression is associated with poor clinical features in LGG patients, and an independent risk factor for overall survival among LGG patients. GSEA results showed that the poor prognostic role of GDF15 in LGGs is related to hypoxia and glycolysis signatures, which was further validated using the hypoxia risk model. Furthermore, GDF15 overexpression facilitated cell proliferation, while GDF15 siRNA inhibits cell proliferation in LGG SW1783 cells. In addition, GDF15 was upregulated upon CoCl2 treatment which induces hypoxia, correlating with the upregulation of the expressions of HIF-1 alpha and glycolysis-related key genes in SW1783 cells.Significance: GDF15 may promote LGG tumorigenesis that is associated with the hypoxia and glycolysis pathways, and thus could serve as a promising molecular target for LGG prevention and therapy.