Abstract
PurposeDual-specificity protein phosphatases 26 (DUSP26) is a recently identified phosphatase enzyme that regulates MAPK and Akt signaling pathways. The role of DUSP26 in the development and prognosis of high-grade gliomas (HGGs) and primary glioblastoma (GBM) has remained unclear and was the focus of this study.Materials and MethodsThe prognostic value of DUSP26 was assessed using retrospective analyses using online data sets and tissue microarray of HGGs. U251 and U87 cells modified to overexpress DUSP26 were utilized to study the role of DUSP26 in cell growth, migration, and cell apoptosis analyzed by CCK-8 assay, clonogenic, transwell migration, and TUNEL, respectively. The phosphorylation of proteins in MAPK and Akt signaling pathways was assayed by Western blot and immunofluorescence assays.ResultsAnalyses using available online data sets and tissue microarray showed that DUSP26 is down-regulated in high-grade gliomas and GBM as compared to normal brain. Stratification of glioma patients based on DUSP26 expression level showed an inverse correlation between DUSP26 expression and patient survival. At the cellular level, DUSP26 overexpression led to decreased cell proliferation, migration, and senescence in U251 and U87 cells, whereas apoptosis was increased as compared to corresponding controls. Interestingly, the biologic effects of DUSP26 overexpression were associated with the dephosphorylation of proteins in the MAPK and Akt signaling pathways.ConclusionsThese findings suggest that the loss of DUSP26 expression, seen in a subset of high-grade gliomas and GBM patients, facilitates malignant behavior; and with inverse correlation between its expression levels with patient survival. DUSP26 can serve as an independent prognostic factor.
Highlights
High-grade gliomas (HGGs), especially the glioblastomas (GBM), represent the most aggressive primary brain cancer in adults
These findings suggest that the loss of Dual-specificity protein phosphatases 26 (DUSP26) expression, seen in a subset of high-grade gliomas and GBM patients, facilitates malignant behavior; and with inverse correlation between its expression levels with patient survival
Since normal cells within tumor microenvironment may account toward DUSP26 expression profiling by RNA-sequencing, estimate to DUSP26 mRNA seen in GBM tissues may not be a true estimate of DUSP26 levels in GBM cells
Summary
High-grade gliomas (HGGs), especially the glioblastomas (GBM), represent the most aggressive primary brain cancer in adults. Activation of the mitogen‐activated protein kinase (MAPK) signaling pathway, which includes c‐Jun NH2‐terminal kinase (JNK), the p38 MAPK, and the extra‐cellular signal‐related kinase (ERK), has been implicated in the development and progression of HGGs, including GBM [3]. The largescale genomic analyses have uncovered activating mutations in the PI3K-Akt signaling pathway [4]. A number of inhibitors targeting MAPK and AKT signaling pathways have been developed, and despite promising results in preclinical studies or these agents had limited efficacy in clinical trials in patients with GBM [5, 6]. MAPK and Akt are independently activated, signaling events often converge in a spatiotemporal manner, and crosstalk between signaling pathways is known to facilitate tumor growth and progression [7]. Understanding molecular mechanisms that allow sustained pro-growth signaling in cancer cells is imperative to facilitate drug development
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