RRC ID 78749
Author Fukasawa K, Lyu J, Kubo T, Tanaka Y, Suzuki A, Horie T, Tomizawa A, Osumi R, Iwahashi S, Tokumura K, Murata M, Kobayashi M, Todo T, Hirao A, Hinoi E.
Title MEK5-ERK5 Axis Promotes Self-renewal and Tumorigenicity of Glioma Stem Cells.
Journal Cancer Res Commun
Abstract UNLABELLED:Glioma stem cells (GSC) promote the malignancy of glioblastoma (GBM), the most lethal brain tumor. ERK5 belongs to the MAPK family. Here, we demonstrated that MAPK kinase 5 (MEK5)-ERK5-STAT3 pathway plays an essential role in maintaining GSC stemness and tumorigenicity by integrating genetic and pharmacologic manipulation and RNA sequencing analysis of clinical specimens. ERK5 was highly expressed and activated in GSCs. ERK5 silencing by short hairpin RNA in GSCs suppressed the self-renewal potential and GBM malignant growth concomitant with downregulation of STAT3 phosphorylation. Conversely, the activation of the MEK5-ERK5 pathway by introducing ERK5 or MEK5 resulted in increased GSC stemness. The introduction of STAT3 counteracted the GSC phenotypes by ERK5 silencing. Moreover, ERK5 expression and signaling are associated with poor prognosis in patients with GBM with high stem cell properties. Finally, pharmacologic inhibition of ERK5 significantly inhibited GSC self-renewal and GBM growth. Collectively, these findings uncover a crucial role of the MEK5-ERK5-STAT3 pathway in maintaining GSC phenotypes and GBM malignant growth, thereby providing a potential target for GSC-directed therapy.
SIGNIFICANCE:In this study, we demonstrated that MEK5-ERK5-STAT3 axis plays a critical role in maintaining stemness and tumorigenicity in GSCs by using genetic, pharmacologic, and bioinformatics tools, identifying the MEK5-ERK5-STAT3 axis as a potential target for GSC-directed therapy.
Volume 3(1)
Pages 148-159
Published 2023-1-1
DOI 10.1158/2767-9764.CRC-22-0243
PII CRC-22-0243
PMID 36968222
PMC PMC10035453
MeSH Cell Line, Tumor Glioblastoma* / genetics Glioma* / genetics Humans Mitogen-Activated Protein Kinase Kinases / metabolism Neoplastic Stem Cells / metabolism
Human and Animal Cells 293T(RCB2022) 293gp(RCB2354)