PAK3 is a key signature gene of the glioma proneural subtype and affects its proliferation, differentiation and growth.
Animals
Biomarkers, Tumor
/ metabolism
Cell Differentiation
/ genetics
Cell Line, Tumor
Cell Proliferation
/ genetics
Chromosome Deletion
Female
Gene Expression Regulation, Neoplastic
Glioma
/ genetics
Isocitrate Dehydrogenase
/ genetics
Mice, Nude
Mutation
/ genetics
Neurons
/ metabolism
Oligodendroglioma
/ genetics
RNA, Small Interfering
/ metabolism
Survival Analysis
p21-Activated Kinases
/ genetics
Glioma tumor growth
Gliomas
Patient-derived cell line
Proliferation and neuronal differentiation
Proneural signature
p21-activated kinase
Journal
Cellular oncology (Dordrecht)
ISSN: 2211-3436
Titre abrégé: Cell Oncol (Dordr)
Pays: Netherlands
ID NLM: 101552938
Informations de publication
Date de publication:
Dec 2021
Dec 2021
Historique:
accepted:
01
09
2021
pubmed:
23
9
2021
medline:
9
3
2022
entrez:
22
9
2021
Statut:
ppublish
Résumé
Gliomas are the most lethal adult primary brain cancers. Recent advances in their molecular characterization have contributed to a better understanding of their pathophysiology, but there is still a need to identify key genes controling glioma cell proliferation and differentiation. The p21-activated kinases PAK1 and PAK2 play essential roles in cell division and brain development and are well-known oncogenes. In contrast, the role of PAK3 in cancer is poorly understood. It is known, however, that this gene is involved in brain ontogenesis and has been identified as a gene of the proneural subtype signature in glioblastomas. To better understand the role of PAK kinases in the pathophysiology of gliomas, we conducted expression analyses by querying multiple gene expression databases and analyzing primary human glioma samples. We next studied PAK3 expression upon differentiation in patient-derived cell lines (PDCLs) and the effects of PAK3 inhibition by lentiviral-mediated shRNA on glioma cell proliferation, differentiation and tumor growth. We show that contrary to PAK1 and PAK2, high PAK3 expression positively correlates with a longer survival of glioma patients. We also found that PAK3 displays differential expression patterns between glioma sub-groups with a higher expression in 1p/19q-codeleted oligodendrogliomas, and is highly expressed in tumors and PDCLs of the proneural subtype. In PDCLs, high PAK3 expression negatively correlated with proliferation and positively correlated with neuronal differentiation. Inhibition of PAK3 expression increased PDCL proliferation and glioma tumor growth in nude mice. Our results indicate that PAK3 plays a unique role among PAKs in glioma development and may represent a potential therapeutic target.
Identifiants
pubmed: 34550532
doi: 10.1007/s13402-021-00635-8
pii: 10.1007/s13402-021-00635-8
doi:
Substances chimiques
Biomarkers, Tumor
0
RNA, Small Interfering
0
Isocitrate Dehydrogenase
EC 1.1.1.41
IDH1 protein, human
EC 1.1.1.42.
Pak3 protein, mouse
EC 2.7.11.1
p21-Activated Kinases
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1257-1271Subventions
Organisme : ARC
ID : PJA2013200481, PJA20151203259
Organisme : ARC
ID : fellowship
Organisme : Agence Nationale de la Recherche
ID : ANR-10-IAIHU-06, ANR-11-INBS-0011
Informations de copyright
© 2021. Springer Nature Switzerland AG.
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