Essential Role of Gli Proteins in Glioblastoma Multiforme

Abstract

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults. Despite several advances, little is known about GBM-specific aberrant signalling processes. The hedgehog (Hh) signalling pathway plays a central role in GBM pathogenesis and tumor progression. Its activation is mediated by sonic hedgehog (Shh), which binds to its receptor patched, PTCH, promoting Gli1 activation. Gli1 is a member of the Kruppel family of zinc finger transcription factors. Hh/Gli1 axis controls glioma stem cells (GSCs) behaviour, which is essential to GBM chemoand radioresistance. Thus, Gli1 modulates the expression of stemness genes and the self-renewal of CD133(+) GSCs. The activation of Hh/Gli1 in GSCs seems to be dependent on the insulin-like growth factor (IGF) signaling, which also contributes to intrinsic and acquired resistance of GSCs to temozolomide (TMZ). Beyond Hh signals, Gli1 activity is also regulated by several elements, including Ras, Myc, Akt, p53 and PTEN. Recently, a truncated variant of Gli1 (tGli1) has been demonstrated to gain the ability to regulate expression of genes that are not modulated by Gli1, such as the migration/invasion-associated CD24 or the human vascular endothelial growth factor-A (VEGF-A), leading to their upregulation. This review will summarize the role of Gli proteins in GBM tumorigenesis and their potential impact on GBM therapy and treatment resistance.