Ligand-dependent EphB1 signaling suppresses glioma invasion and correlates with patient survival

Nakada, Mitsutoshi; Furuyama, Natsuki; Sabit, Hemragul; Furuta, Takeshi; Hayashi, Yutaka; Takino, Takahisa; Dong, Yu; Sato, Hiroshi; Sai, Yoshimichi; Miyamoto, Ken‐ichi; Berens, Michael E.; Hamada, Jun-ichiro

doi:10.1093/neuonc/not128

Cited by 29 publications

(36 citation statements)

References 36 publications

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“…Approximately 1 μg RNA was used to synthesize cDNA. The gene expression levels of p68 and DUSP5 were determined by quantitative real‐time PCR (qRT‐PCR) and analyzed using LightCycler analysis software (Roche, Basel, Switzerland), and GAPDH was used as the endogenous control . Quantitative RT‐PCR was carried out with the following primers: p68 sense (GenBank accession no.…”

Section: Methodsmentioning

confidence: 99%

P68 RNA helicase promotes invasion of glioma cells through negatively regulating DUSP5

Wang

Bao

et al. 2018

Cancer Science

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Gliomas are the most common central nervous system tumors. They show malignant characteristics indicating rapid proliferation and a high invasive capacity and are associated with a poor prognosis. In our previous study, p68 was overexpressed in glioma cells and correlated with both the degree of glioma differentiation and poor overall survival. Downregulating p68 significantly suppressed proliferation in glioma cells. Moreover, we found that the p68 gene promoted glioma cell growth by activating the nuclear factor‐κB signaling pathway by a downstream molecular mechanism that remains incompletely understood. In this study, we found that dual specificity phosphatase 5 (DUSP5) is a downstream target of p68, using microarray analysis, and that p68 negatively regulates DUSP5. Upregulating DUSP5 in stably expressing cell lines (U87 and LN‐229) suppressed proliferation, invasion, and migration in glioma cells in vitro, consistent with the downregulation of p68. Furthermore, upregulating DUSP5 inhibited ERK phosphorylation, whereas downregulating DUSP5 rescued the level of ERK phosphorylation, indicating that DUSP5 might negatively regulate ERK signaling. Additionally, we show that DUSP5 levels were lower in high‐grade glioma than in low‐grade glioma. These results suggest that the p68‐induced negative regulation of DUSP5 promoted invasion by glioma cells and mediated the activation of the ERK signaling pathway.

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Section: Methodsmentioning

confidence: 99%

P68 RNA helicase promotes invasion of glioma cells through negatively regulating DUSP5

Wang

Bao

et al. 2018

Cancer Science

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“…However, c-Cbl mutations do not frequently occur in pediatric AML (33). The tumor-suppressor function of EphB1 in AML and the association in a variety of cancers between loss of expression and aggressive tumor phenotypes implies that EphB1 is an important regulator of common cancer cell–transforming pathways (12, 13, 34). Conformingly, we used the MethHC DNA methylation database in human cancers (35) to analyze EphB1 promoter CpG site methylation and found common promoter hypermethylation enriched at the 5′ untranslated regions (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

EphB1 Suppression in Acute Myelogenous Leukemia: Regulating the DNA Damage Control System

Kampen

Scherpen

Garcia‐Manero

et al. 2015

Molecular Cancer Research

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Loss of ephrin receptor (EphB1) expression may associate with aggressive cancer phenotypes; however, the mechanism of action remains unclear. To gain detailed insight into EphB1 function in acute myelogenous leukemia (AML), comprehensive analysis of EphB1 transcriptional regulation was conducted. In AML cells, EphB1 transcript was inversely correlated with EphB1 promoter methylation. The presence of EphB1 allowed EfnB1 ligand–mediated p53 DNA binding, leading to restoration of the DNA damage response (DDR) cascade by the activation of ATR, Chk1, p53, p21, p38, CDK1tyr15, and Bax, and downregulation of HSP27 and Bcl2. Comparatively, reintroduction of EphB1 expression in EphB1-methylated AML cells enhanced the same cascade of ATR, Chk1, p21, and CDK1tyr15, which consequently enforced programmed cell death. Interestingly, in pediatric AML samples, EphB1 peptide phosphorylation and mRNA expression were actively suppressed as compared with normal bone marrow, and a significant percentage of the primary AML specimens had EphB1 promoter hyper-methylation. Finally, EphB1 repression associated with a poor overall survival in pediatric AML. Combined, the contribution of EphB1 to the DDR system reveals a tumor-suppressor function for EphB1 in pediatric AML. Implications The tumor-suppressor function of EphB1 is clinically relevant across many malignancies, suggesting that EphB1 is an important regulator of common cancer cell trans forming pathways.

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“…PASD1, a coexpression gene of ZIC3, promotes glioma cell proliferation by inhibiting apoptosis in vitro [36]. EphB1 is activated by ZIC2 and negatively regulates glioma cell invasion as a favourable prognostic factor [37]. ZIC proteins are critical in cerebellar development, and the ZIC-related autoimmune response impacts the pathogenesis of neurologic disorders [38].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional expression of ZICs as an independent indicator of survival in gliomas

Han

Jia

et al. 2020

Preprint

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Background: The functional significance of the zinc-finger of the cerebellum (ZIC) gene family in gliomas remains to be elucidated. Methods: Clinical data from patients with gliomas, containing expression levels of ZIC genes, were extracted from CCLE, GEPIA2 and The Human Protein Atlas(HPA). Univariate survival analysis adjusted by Cox regression via OncoLnc was used to determine the prognostic significance of ZIC expression. We used cBioPortal to explore the correlation between gene mutations and overall survival (OS). ZIC expression was found to be related to immune cell infiltration in gliomas via TIMER analysis. GO term and KEGG pathway enrichment analyses were performed with Metascape. PPI networks were constructed using STRING. Result: The expression levels of ZIC1/2/4 in gliomas were significantly different from those in normal samples. High expression levels of ZIC1/2/5 were associated with poor OS in brain low-grade glioma (LGG) patients, while low ZIC3 expression combined with high ZIC4 expression was related to favourable OS in glioblastoma multiforme (GBM). ZIC mutations were associated with poor prognosis in LGG patients and related to favourable prognosis in GBM patients. We observed that the expression of ZICs was related to immune cell infiltration in glioma patients. ZICs were enriched in several pathways and biological processes involving arrhythmogenic right ventricular cardiomyopathy (ARVC) and tissue morphogenesis. The PPI network revealed that some coexpressed proteins of ZICs played a role in the pathogenesis of gliomas. Conclusions: Differences in the expression levels of ZIC genes could provide a significant marker for predicting prognosis in gliomas.

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Ligand-dependent EphB1 signaling suppresses glioma invasion and correlates with patient survival

Abstract: These data suggest that ligand-dependent EphB1 signaling negatively regulates glioma cell invasion, identifying EphB1 as a favorable prognostic factor in malignant glioma.

Cited by 29 publications

References 36 publications

P68 RNA helicase promotes invasion of glioma cells through negatively regulating DUSP5

P68 RNA helicase promotes invasion of glioma cells through negatively regulating DUSP5

EphB1 Suppression in Acute Myelogenous Leukemia: Regulating the DNA Damage Control System

Transcriptional expression of ZICs as an independent indicator of survival in gliomas

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