Abstract
Glioblastomas (GBMs), the most aggressive primary brain tumors, exhibit increased invasiveness and resistance to anti-tumor treatments. We explored the role of RTVP-1, a glioma-associated protein that promotes glioma cell migration, in the mesenchymal transformation of GBM. Analysis of The Cancer Genome Atlas (TCGA) demonstrated that RTVP-1 expression was higher in mesenchymal GBM and predicted tumor recurrence and poor clinical outcome. ChiP analysis revealed that the RTVP-1 promoter binds STAT3 and C/EBPβ, two master transcription factors that regulate mesenchymal transformation of GBM. In addition, IL-6 induced RTVP-1 expression in a STAT3-dependent manner. RTVP-1 increased the migration and mesenchymal transformation of glioma cells. Similarly, overexpression of RTVP-1 in human neural stem cells induced mesenchymal differentiation, whereas silencing of RTVP-1 in glioma stem cells (GSCs) decreased the mesenchymal transformation and stemness of these cells. Silencing of RTVP-1 also increased the survival of mice bearing GSC-derived xenografts. Using gene array analysis of RTVP-1 silenced glioma cells we identified IL-6 as a mediator of RTVP-1 effects on the mesenchymal transformation and migration of GSCs, therefore acting in a positive feedback loop by upregulating RTVP-1 expression via the STAT3 pathway. Collectively, these results implicate RTVP-1 as a novel prognostic marker and therapeutic target in GBM.
Highlights
Glioblastoma (GBM) are the most common and aggressive astrocytic tumors and are characterized by increased proliferation, invasion into the surrounding normal tissue, robust angiogenesis and resistance to conventional therapies [1]
We further examined the role of RTVP-1 in glioma cell migration and in the mesenchymal transformation of these cells
We first examined whether RTVP-1 expression was associated with the mesenchymal subtype of GBM, which is known to be associated with increased degree of infiltration and predicts poor clinical outcome
Summary
Glioblastoma (GBM) are the most common and aggressive astrocytic tumors and are characterized by increased proliferation, invasion into the surrounding normal tissue, robust angiogenesis and resistance to conventional therapies [1]. The prognosis of patients with GBM remains extremely poor and has not changed significantly during the past several years [2, 3]. GSCs have been implicated in treatment resistance and tumor recurrence of GBM [7]. Gene expression profiling studies have identified four GBM subtypes that were classified based on their transcriptional signatures into proneural, neural, classical and mesenchymal subtypes [8,9,10,11,12]. These subtypes have distinct differential genetic alterations, molecular signature, cellular phenotypes and patient prognosis. These subtypes have distinct differential genetic alterations, molecular signature, cellular phenotypes and patient prognosis. [9, 13,14,15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
