ABSTRACT
To date, the mutational status of EGFR and PTEN has been shown as relevant for favoring pro- or anti-tumor functions of STAT3 in human glioblastoma multiforme (GBM). We have screened genomic data from 154 patients and have identified a strong positive correlation between STAT3 and HDAC7 expression. In the current work we show the existence of a subpopulation of patients overexpressing HDAC7 and STAT3 that has particularly poor clinical outcome. Surprisingly, the somatic mutation rate of both STAT3 and HDAC7 was insignificant in GBM comparing with EGFR, PTEN or TP53. Depletion of HDAC7 in a range of GBM cells induced the expression of tyrosine kinase JAK1 and the tumor suppressor AKAP12. Both proteins synergistically sustained the activity of STAT3 by inducing its phosphorylation (JAK1) and protein expression (AKAP12). In absence of HDAC7, activated STAT3 was responsible for significant imbalance of secreted pro-/anti-angiogenic factors. This inhibited the migration and sprouting of endothelial cells in paracrine fashion in vitro as well as angiogenesis in vivo. In a murine model of GBM, induced HDAC7-silencing decreased the tumor burden by threefold. The current data show for the first time that silencing HDAC7 can reset the tumor suppressor activity of STAT3, independently of the EGFR/PTEN/TP53 background of the GBM. This effect could be exploited to overcome tumor heterogeneity and provide a new rationale behind the development of specific HDAC7 inhibitors for clinical use.
Subject(s)
ErbB Receptors/physiology , Glioblastoma/pathology , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/physiology , PTEN Phosphohydrolase/physiology , STAT3 Transcription Factor/physiology , A Kinase Anchor Proteins/physiology , Animals , Brain/pathology , Cell Cycle Proteins/physiology , Cell Line, Tumor , Glioblastoma/drug therapy , Histone Deacetylase Inhibitors/therapeutic use , Histone Deacetylases/analysis , Humans , Janus Kinase 1/physiology , Male , Mice , Neovascularization, Pathologic/prevention & control , STAT3 Transcription Factor/analysisABSTRACT
Technological innovations have endowed the development of powerful tools in medical imaging, such as transcranial color-coded sonography. In addition to other imaging techniques, its relevance in cerebrovascular disorders is increasing. This article aims to describe the technique through specification of its current indications in patients with arterial cervical and intracranial stenosis.
