shRNA ‐mediated PPARα knockdown in human glioma stem cells reduces in vitro proliferation and inhibits orthotopic xenograft tumour growth

AbstractThe overall survival for patients with primary glioblastoma is very poor. Glioblastoma contains a subpopulation of glioma stem cells (GSC) which are responsible for tumour initiation, treatment resistance and recurrence. PPAR α is a transcription factor involved in control of lipid, carbohydrate and amino acid metabolism. We have recently shown that PPARα gene and protein expression is increased in glioblastoma and has independent clinical prognostic significance in multivariate analyses. In this work we report that PP ARα is overexpressed in GSC compared to foetal neural stem cells. To investigate the role of PPARα in GSC we knocked down its expression using lentiviral transduction with short hairpin RNA (shRNA). Transduced GSC were tagged with luciferase and stereotactically xenografted into the striatum of NO D‐SCID mice. Bioluminescent and magnetic resonance imaging showed that knockdown (KD) of PPARα reduced the tumorigenicity of GSCin vivo. PPAR α expressing control GSC xenografts formed invasive histological phenocopies of human glioblastoma, whereas PPARα KD GSC xenografts failed to establish viable intracranial tumours. PPARα KD GSC showed significantly reduced proliferative capacity and clonogenic potentialin vitro with an increase in cellular senescence. In addition, PPAR α KD resulted in significant downregulation of the stem cell factors c‐Myc, nestin and SOX2. This was accompanied by downregulation of the PPARα‐target genes and key regula...
Source: The Journal of Pathology - Category: Pathology Authors: Tags: Original Paper Source Type: research