shRNA-mediated PPARα knockdown in human glioma stem cells reduces in vitro proliferation and inhibits orthotopic xenograft tumour growth.
Animals
Biomarkers, Tumor
/ metabolism
Brain Neoplasms
/ pathology
Cell Transformation, Neoplastic
Down-Regulation
Female
Gene Expression Regulation, Neoplastic
/ physiology
Gene Knockdown Techniques
/ methods
Glioblastoma
/ pathology
Humans
Lentivirus
Mice, Inbred NOD
Mice, SCID
Neoplastic Stem Cells
/ pathology
PPAR alpha
/ metabolism
Phenotype
RNA, Small Interfering
/ pharmacology
Signal Transduction
/ physiology
Transplantation, Heterologous
Tumor Cells, Cultured
PPARα
glioma stem cell
shRNA
Journal
The Journal of pathology
ISSN: 1096-9896
Titre abrégé: J Pathol
Pays: England
ID NLM: 0204634
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
26
06
2018
revised:
18
10
2018
accepted:
13
11
2018
pubmed:
20
12
2018
medline:
18
12
2019
entrez:
20
12
2018
Statut:
ppublish
Résumé
The overall survival for patients with primary glioblastoma is very poor. Glioblastoma contains a subpopulation of glioma stem cells (GSC) that are responsible for tumour initiation, treatment resistance and recurrence. PPARα is a transcription factor involved in the 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 PPARα 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 NOD-SCID mice. Bioluminescent and magnetic resonance imaging showed that knockdown (KD) of PPARα reduced the tumourigenicity of GSC in vivo. PPARα-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 potential in vitro with an increase in cellular senescence. In addition, PPARα 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 regulators of fatty acid oxygenation ACOX1 and CPT1A, with no compensatory increase in glycolytic flux. These data establish the aberrant overexpression of PPARα in GSC and demonstrate that this expression functions as an important regulator of tumourigenesis, linking self-renewal and the malignant phenotype in this aggressive cancer stem cell subpopulation. We conclude that targeting GSC PPARα expression may be a therapeutically beneficial strategy with translational potential as an adjuvant treatment. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Identifiants
pubmed: 30565681
doi: 10.1002/path.5201
pmc: PMC6462812
doi:
Substances chimiques
Biomarkers, Tumor
0
PPAR alpha
0
RNA, Small Interfering
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
422-434Subventions
Organisme : Medical Research Council
ID : G0701018
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council (BBSRC)
ID : BB/M017532
Pays : International
Organisme : Medical Research Council
ID : MR/N004272/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 10065
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1100578
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N001370/1
Pays : United Kingdom
Informations de copyright
© 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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