Signal transducer and activator of transcription 5b drives malignant progression in a PDGFB‐dependent proneural glioma model by suppressing apoptosis

Abstract

Signal transducer and activator of transcription 5b (STAT5b) is likely the relevant STAT5 isoform with respect to the process of malignant progression in gliomas. STAT5b is a latent cytoplasmic protein involved in cell signaling through the modulation of growth factors, apoptosis, and angiogenesis. Previous in vitro studies have shown increased STAT5b expression in glioblastomas relative to low-grade tumors and normal brain. We recently demonstrated that phosphorylated STAT5b associates with delta epidermal growth factor receptor in the nucleus and subsequently binds the promoters of downstream effector molecules, including aurora kinase A. Analysis of TCGA dataset reveals that STAT5b is predominantly expressed in proneural (PN) gliomas relative to mesenchymal and neural gliomas. Here, we modeled ectopic expression of STAT5b in vivo using a platelet-derived growth factor subunit B (PDGFB)-dependent mouse model of PN glioma to determine its effect on tumor formation and progression. We showed that co-expression of STAT5b and PDGFB in mice yielded a significantly higher rate of high-grade gliomas than PDGFB expression alone. We also observed shorter survival in the combined expression set. High-grade tumors from the STAT5b+PDGFB expression set were found to have a lower rate of apoptosis than those from PDGFB alone. Furthermore, we showed that increased expression of STAT5b+PDGFB led to increased expression of downstream STAT5b targets, including Bcl-xL, cyclin D1, and aurora kinase A in high-grade tumors when compared to tumors derived from PDGFB alone. Our findings show that STAT5b promotes the malignant transformation of gliomas, particularly the PN subtype, and is a potential therapeutic target.

Identification of a Dexamethasone Mediated Radioprotection Mechanism Reveals New Therapeutic Vulnerabilities in Glioblastoma

“…In fact, STAT5B can be activated by SFKs and mediate survival signalling in glioblastoma cells through direct activation of the BCL2L1 promoter [ 28 ]. Moreover, STAT5B can drive tumour progression in a PDGFB-driven glioma model and this involves increased BCL2L1 expression [ 29 ]. In the TCGA GBM patient cohort [ 4 ] STAT5B and the expression of SRC, FYN and YES are strongly correlated with the expression of BCL2L1, but also with MCL1 ( Figure 3 F and Figure S4A ).…”

Epilepsy Associates with Decreased HIF-1α/STAT5b Signaling in Glioblastoma

“…Also, crosstalk between HIF-1α and STAT3 was reported, in different tumor types, including glioblastoma [33,34]. Interest in STAT5 signaling in glioblastoma is growing, as multiple studies have shown that STAT5b drives proliferation and invasion in glioma [35,36,37,38]. This may be, in part mediated by the oncogenic EGFRvIII variant [39,40,41].…”

Analysis of the inhibitors of apoptosis identifies BIRC3 as a facilitator of malignant progression in glioma

“…We co-expressed BIRC3 and PDGFB and independently in Ntv-a mice. Consistent with our previous studies mice were humanely euthanized by carbon dioxide asphyxiation 90 days post-injection or sooner if symptoms related to tumor burden (e.g., hydrocephalus) were present [5, 11, 36]. The brains were removed, fixed in formalin, embedded in paraffin, and sectioned for immunohistochemical analysis.…”