MEK5-ERK5 Axis Promotes Self-renewal and Tumorigenicity of Glioma Stem Cells

被引：5

作者：

Fukasawa, Kazuya ^{[1
,7
]}

Lyu, Jiajun ^{[1
]}

Kubo, Takuya ^{[1
]}

Tanaka, Yuki ^{[1
]}

Suzuki, Akane ^{[1
]}

Horie, Tetsuhiro ^{[2
]}

Tomizawa, Akane ^{[1
]}

Osumi, Ryoma ^{[1
]}

Iwahashi, Sayuki ^{[1
]}

Tokumura, Kazuya ^{[1
]}

Murata, Misato ^{[1
]}

Kobayashi, Masaki ^{[1
]}

Todo, Tomoki ^{[3
]}

Hirao, Atsushi ^{[4
,5
]}

Hinoi, Eiichi ^{[1
,6
,7
]}

机构：

[1] Gifu Pharmaceut Univ, Dept Bioact Mol, Lab Pharmacol, Gifu, Japan

[2] Kanazawa Med Univ, Med Res Inst, Kahoku, Ishikawa, Japan

[3] Univ Tokyo, Inst Med Sci, Div Innovat Canc Therapy, Tokyo, Japan

[4] Kanazawa Univ, WPI Nano Life Sci Inst WPI Nano LSI, Kanazawa, Ishikawa, Japan

[5] Kanazawa Univ, Canc Res Inst, Canc & Stem Cell Res Program, Div Mol Genet, Kanazawa, Ishikawa, Japan

[6] Gifu Univ, United Grad Sch Drug Discovery & Med Informat Sci, Gifu, Japan

[7] Gifu Pharmaceut Univ, Gifu 5011196, Japan

来源：

CANCER RESEARCH COMMUNICATIONS | 2023年 / 3卷 / 01期

关键词：

SUPPRESSES TUMOR-GROWTH; SIGNALING PATHWAY; CANCER CELLS; OVEREXPRESSION; PROLIFERATION; POPULATION; INHIBITION; ACTIVATION;

D O I：

10.1158/2767-9764.CRC-22-0243

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：148 / 159

页数：12