Peroxisome proliferator-activated receptor gamma as a theragnostic target for mesenchymal-type glioblastoma patients.
Animals
Antineoplastic Agents
/ pharmacology
Biomarkers, Tumor
/ antagonists & inhibitors
Cell Line, Tumor
Cell Proliferation
Disease Models, Animal
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Glioblastoma
/ diagnosis
Humans
Mice
PPAR gamma
/ antagonists & inhibitors
Prognosis
RNA, Small Interfering
/ genetics
Signal Transduction
Transcriptome
Xenograft Model Antitumor Assays
Journal
Experimental & molecular medicine
ISSN: 2092-6413
Titre abrégé: Exp Mol Med
Pays: United States
ID NLM: 9607880
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
17
10
2019
accepted:
19
02
2020
revised:
17
02
2020
pubmed:
14
4
2020
medline:
3
8
2021
entrez:
14
4
2020
Statut:
ppublish
Résumé
Glioblastomas (GBMs) are characterized by four subtypes, proneural (PN), neural, classical, and mesenchymal (MES) GBMs, and they all have distinct activated signaling pathways. Among the subtypes, PN and MES GBMs show mutually exclusive genetic signatures, and the MES phenotype is, in general, believed to be associated with more aggressive features of GBM: tumor recurrence and drug resistance. Therefore, targeting MES GBMs would improve the overall prognosis of patients with fatal tumors. In this study, we propose peroxisome proliferator-activated receptor gamma (PPARγ) as a potential diagnostic and prognostic biomarker as well as therapeutic target for MES GBM; we used multiple approaches to assess PPARγ, including biostatistics analysis and assessment of preclinical studies. First, we found that PPARγ was exclusively expressed in MES glioblastoma stem cells (GSCs), and ligand activation of endogenous PPARγ suppressed cell growth and stemness in MES GSCs. Further in vivo studies involving orthotopic and heterotopic xenograft mouse models confirmed the therapeutic efficacy of targeting PPARγ; compared to control mice, those that received ligand treatment exhibited longer survival as well as decreased tumor burden. Mechanistically, PPARγ activation suppressed proneural-mesenchymal transition (PMT) by inhibiting the STAT3 signaling pathway. Biostatistical analysis using The Cancer Genomics Atlas (TCGA, n = 206) and REMBRANDT (n = 329) revealed that PPARγ upregulation is linked to poor overall survival and disease-free survival of GBM patients. Analysis was performed on prospective (n = 2) and retrospective (n = 6) GBM patient tissues, and we finally confirmed that PPARγ expression was distinctly upregulated in MES GBM. Collectively, this study provides insight into PPARγ as a potential therapeutic target for patients with MES GBM.
Identifiants
pubmed: 32280134
doi: 10.1038/s12276-020-0413-1
pii: 10.1038/s12276-020-0413-1
pmc: PMC7210935
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers, Tumor
0
PPAR gamma
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
629-642Subventions
Organisme : National Research Foundation of Korea (NRF)
ID : NRF-2016R1D1A3B03930581
Pays : International
Organisme : National Research Foundation of Korea (NRF)
ID : NRF-2017R1A5A2015369
Pays : International
Organisme : National Research Foundation of Korea (NRF)
ID : 2017M2A2A7A02019
Pays : International
Organisme : Korea Health Industry Development Institute (KHIDI)
ID : HI17C0039
Pays : International
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