PMID- 30565681
OWN - NLM
STAT- MEDLINE
DCOM- 20191216
LR  - 20210217
IS  - 1096-9896 (Electronic)
IS  - 0022-3417 (Print)
IS  - 0022-3417 (Linking)
VI  - 247
IP  - 4
DP  - 2019 Apr
TI  - shRNA-mediated PPARalpha knockdown in human glioma stem cells reduces in vitro 
      proliferation and inhibits orthotopic xenograft tumour growth.
PG  - 422-434
LID - 10.1002/path.5201 [doi]
AB  - 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. PPARalpha is 
      a transcription factor involved in the control of lipid, carbohydrate and amino 
      acid metabolism. We have recently shown that PPARalpha gene and protein expression is 
      increased in glioblastoma and has independent clinical prognostic significance in 
      multivariate analyses. In this work, we report that PPARalpha is overexpressed in GSC 
      compared to foetal neural stem cells. To investigate the role of PPARalpha 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 PPARalpha reduced the tumourigenicity 
      of GSC in vivo. PPARalpha-expressing control GSC xenografts formed invasive 
      histological phenocopies of human glioblastoma, whereas PPARalpha KD GSC xenografts 
      failed to establish viable intracranial tumours. PPARalpha KD GSC showed 
      significantly reduced proliferative capacity and clonogenic potential in vitro 
      with an increase in cellular senescence. In addition, PPARalpha KD resulted in 
      significant downregulation of the stem cell factors c-Myc, nestin and SOX2. This 
      was accompanied by downregulation of the PPARalpha-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 PPARalpha 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 PPARalpha 
      expression may be a therapeutically beneficial strategy with translational 
      potential as an adjuvant treatment. (c) 2018 The Authors. The Journal of Pathology 
      published by John Wiley & Sons Ltd on behalf of Pathological Society of Great 
      Britain and Ireland.
CI  - (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd 
      on behalf of Pathological Society of Great Britain and Ireland.
FAU - Haynes, Harry R
AU  - Haynes HR
AUID- ORCID: 0000-0001-6468-7671
AD  - Brain Tumour Research Group, Translational Health Sciences, Bristol Medical 
      School, University of Bristol, Bristol, UK.
AD  - Department of Cellular Pathology, North Bristol NHS Trust, Bristol, UK.
FAU - Scott, Helen L
AU  - Scott HL
AD  - Translational Health Sciences, Bristol Medical School, University of Bristol, 
      Bristol, UK.
FAU - Killick-Cole, Clare L
AU  - Killick-Cole CL
AD  - Functional Neurosurgery Research Group, Translational Health Sciences, Bristol 
      Medical School, University of Bristol, Bristol, UK.
FAU - Shaw, Gary
AU  - Shaw G
AD  - Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
FAU - Brend, Tim
AU  - Brend T
AD  - Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
FAU - Hares, Kelly M
AU  - Hares KM
AD  - Multiple Sclerosis and Stem Cell Group, Translational Health Sciences, Bristol 
      Medical School, University of Bristol, Bristol, UK.
FAU - Redondo, Juliana
AU  - Redondo J
AD  - Multiple Sclerosis and Stem Cell Group, Translational Health Sciences, Bristol 
      Medical School, University of Bristol, Bristol, UK.
FAU - Kemp, Kevin C
AU  - Kemp KC
AD  - Multiple Sclerosis and Stem Cell Group, Translational Health Sciences, Bristol 
      Medical School, University of Bristol, Bristol, UK.
FAU - Ballesteros, Lorena S
AU  - Ballesteros LS
AD  - Flow Cytometry Facility, School of Cellular and Molecular Medicine, University of 
      Bristol, Bristol, UK.
FAU - Herman, Andrew
AU  - Herman A
AD  - Flow Cytometry Facility, School of Cellular and Molecular Medicine, University of 
      Bristol, Bristol, UK.
FAU - Cordero-Llana, Oscar
AU  - Cordero-Llana O
AD  - Translational Health Sciences, Bristol Medical School, University of Bristol, 
      Bristol, UK.
FAU - Singleton, William G
AU  - Singleton WG
AD  - Functional Neurosurgery Research Group, Translational Health Sciences, Bristol 
      Medical School, University of Bristol, Bristol, UK.
AD  - Department of Neurosurgery, North Bristol NHS Trust, Bristol, UK.
FAU - Mills, Francesca
AU  - Mills F
AD  - Department of Clinical Biochemistry, North Bristol NHS Trust, Bristol, UK.
FAU - Batstone, Tom
AU  - Batstone T
AD  - Bioinformatics Facility, School of Biological Sciences, University of Bristol, 
      Bristol, UK.
FAU - Bulstrode, Harry
AU  - Bulstrode H
AD  - Department of Clinical Neuroscience and Stem Cell Institute, University of 
      Cambridge, Cambridge, UK.
FAU - Kauppinen, Risto A
AU  - Kauppinen RA
AD  - Clinical Research and Imaging Centre, University of Bristol, Bristol, UK.
FAU - Wurdak, Heiko
AU  - Wurdak H
AD  - Stem Cells and Brain Tumour Group, Leeds Institute of Cancer and Pathology, 
      University of Leeds, Leeds, UK.
FAU - Uney, James B
AU  - Uney JB
AD  - Translational Health Sciences, Bristol Medical School, University of Bristol, 
      Bristol, UK.
FAU - Short, Susan C
AU  - Short SC
AD  - Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
FAU - Wilkins, Alastair
AU  - Wilkins A
AD  - Multiple Sclerosis and Stem Cell Group, Translational Health Sciences, Bristol 
      Medical School, University of Bristol, Bristol, UK.
FAU - Kurian, Kathreena M
AU  - Kurian KM
AD  - Brain Tumour Research Group, Translational Health Sciences, Bristol Medical 
      School, University of Bristol, Bristol, UK.
LA  - eng
GR  - G0701018/MRC_/Medical Research Council/United Kingdom
GR  - BB/M017532/Biotechnology and Biological Sciences Research Council 
      (BBSRC)/International
GR  - MR/N004272/1/MRC_/Medical Research Council/United Kingdom
GR  - 10065/CRUK_/Cancer Research UK/United Kingdom
GR  - G1100578/MRC_/Medical Research Council/United Kingdom
GR  - MR/N001370/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181227
PL  - England
TA  - J Pathol
JT  - The Journal of pathology
JID - 0204634
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (PPAR alpha)
RN  - 0 (RNA, Small Interfering)
SB  - IM
MH  - Animals
MH  - Biomarkers, Tumor/metabolism
MH  - Brain Neoplasms/*pathology
MH  - Cell Transformation, Neoplastic
MH  - Down-Regulation
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/physiology
MH  - Gene Knockdown Techniques/methods
MH  - Glioblastoma/*pathology
MH  - Humans
MH  - Lentivirus
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - Neoplastic Stem Cells/pathology
MH  - PPAR alpha/*metabolism
MH  - Phenotype
MH  - RNA, Small Interfering/*pharmacology
MH  - Signal Transduction/physiology
MH  - Transplantation, Heterologous
MH  - Tumor Cells, Cultured
PMC - PMC6462812
OTO - NOTNLM
OT  - PPARalpha
OT  - glioma stem cell
OT  - shRNA
EDAT- 2018/12/20 06:00
MHDA- 2019/12/18 06:00
PMCR- 2019/04/15
CRDT- 2018/12/20 06:00
PHST- 2018/06/26 00:00 [received]
PHST- 2018/10/18 00:00 [revised]
PHST- 2018/11/13 00:00 [accepted]
PHST- 2018/12/20 06:00 [pubmed]
PHST- 2019/12/18 06:00 [medline]
PHST- 2018/12/20 06:00 [entrez]
PHST- 2019/04/15 00:00 [pmc-release]
AID - PATH5201 [pii]
AID - 10.1002/path.5201 [doi]
PST - ppublish
SO  - J Pathol. 2019 Apr;247(4):422-434. doi: 10.1002/path.5201. Epub 2018 Dec 27.