Oncogenic DIRAS3 promotes malignant phenotypes of glioma by activating EGFR-AKT signaling

Peng, Yong; Jia, Jiaoying; Jiang, Zhongzhong; Huang, Dezhi; Jiang, Yugang; Li, Yun

doi:10.1016/j.bbrc.2018.09.119

Cited by 9 publications

(4 citation statements)

References 16 publications

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“…Instead, another study has shown that DIRAS3 is overexpressed in glioma and is positively associated with adverse outcome of glioma patients. In the meantime, overexpression of DIRAS3 promotes glioma cell proliferation and invasion via EGFR‐AKT signalling pathway . Our study was identical to the opinion that DIRAS3 was correlated with poor prognosis of GBM and was a risk factor for GBM survival.…”

Section: Discussionsupporting

confidence: 87%

A risk signature with four autophagy‐related genes for predicting survival of glioblastoma multiforme

Wang

Zhao

Xiao

et al. 2020

J Cellular Molecular Medi

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Glioblastoma multiforme (GBM) is a devastating brain tumour without effective treatment. Recent studies have shown that autophagy is a promising therapeutic strategy for GBM. Therefore, it is necessary to identify novel biomarkers associated with autophagy in GBM. In this study, we downloaded autophagy-related genes from Human Autophagy Database (HADb) and Gene Set Enrichment Analysis (GSEA) website. Least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analysis were performed to identify genes for constructing a risk signature. A nomogram was developed by integrating the risk signature with clinicopathological factors. Time-dependent receiver operating characteristic (ROC) curve and calibration plot were used to evaluate the efficiency of the prognostic model. Finally, four autophagy-related genes (DIRAS3, LGALS8, MAPK8 and STAM)were identified and were used for constructing a risk signature, which proved to be an independent risk factor for GBM patients. Furthermore, a nomogram was developed based on the risk signature and clinicopathological factors (IDH1 status, age and history of radiotherapy or chemotherapy). ROC curve and calibration plot suggested the nomogram could accurately predict 1-, 3-and 5-year survival rate of GBM patients.For function analysis, the risk signature was associated with apoptosis, necrosis, immunity, inflammation response and MAPK signalling pathway. In conclusion, the risk signature with 4 autophagy-related genes could serve as an independent prognostic factor for GBM patients. Moreover, we developed a nomogram based on the risk signature and clinical traits which was validated to perform better for predicting 1-, 3-and 5-year survival rate of GBM. K E Y W O R D Sautophagy, glioblastoma multiform, nomogram, prognosis, risk signature

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Section: Discussionsupporting

confidence: 87%

A risk signature with four autophagy‐related genes for predicting survival of glioblastoma multiforme

Wang

Zhao

Xiao

et al. 2020

J Cellular Molecular Medi

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“…Studies on the regulation and function of DIRAS-3 have been published on various types of cancers including glioma [20][21][22][23][24][25][26][27]. DIRAS-3 belongs to the same family of small Ras GTPases as DIRAS-1 and -2.…”

Section: Discussionmentioning

confidence: 99%

Frequent Epigenetic Inactivation of DIRAS-1 and DIRAS-2 Contributes to Chemo-Resistance in Gliomas

Rothhammer-Hampl

Liesenberg

Hansen

et al. 2021

Cancers

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We previously reported that DIRAS-3 is frequently inactivated in oligodendrogliomas due to promoter hypermethylation and loss of the chromosomal arm 1p. DIRAS-3 inactivation was associated with better overall survival. Consequently, we now investigated regulation and function of its family members DIRAS-1 and DIRAS-2. We found that DIRAS-1 was strongly downregulated in 65% and DIRAS-2 in 100% of analyzed glioma samples compared to non-neoplastic brain tissue (NNB). Moreover, a significant down-regulation of DIRAS-1 and -2 was detected in glioma data obtained from the TCGA database. Mutational analyses did not reveal any inactivating mutations in the DIRAS-1 and -2 coding regions. Analysis of the DIRAS-1 and -2 promoter methylation status showed significantly higher methylation in IDH-mutant astrocytic and IDH-mutant and 1p/19q-codeleted oligodendroglial tumors compared to NNB. Treatment of U251MG and Hs683 glioblastoma cells lines with 5-azacytidine led to significant re-expression of DIRAS-1 and -2. For IDH-wild-type primary gliomas, however, we did not observe significantly elevated DIRAS-1 and -2 promoter methylation levels, but still detected strong downregulation of both DIRAS family members. Additional analyses revealed that DIRAS-1 and -2 expression was also regulated by histone modifications. We observed a shift towards promoter heterochromatinization for DIRAS-1 and less promoter euchromatinization for DIRAS-2 in IDH-wild-type glioblastomas compared to controls. Treatment of the two glioblastoma cell lines with a histone deacetylase inhibitor led to significant re-expression of DIRAS-1 and -2. Functionally, overexpression of DIRAS-1 and -2 in glioblastoma cells translated into significantly higher sensitivity to lomustine treatment. Analyses of DNA damage markers revealed that DIRAS-1 and -2 may play a role in p53-dependent response to alkylating chemotherapy.

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“…The molecular landscape has detected EGFR gene alterations in more than half of patients with GBM (15). EGFR signaling is required to sustain the uncontrolled proliferation in tumor initiation and progression of GBM (16,17). EGFR gene alteration is associated with the therapy response and clinical survival of GBM patients (18).…”

Section: Introductionmentioning

confidence: 99%

Analysis of the EGFR Amplification and CDKN2A Deletion Regulated Transcriptomic Signatures Reveals the Prognostic Significance of SPATS2L in Patients With Glioma

Wang

et al. 2021

Front. Oncol.

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Purpose: This study was conducted in order to analyze the prognostic effects of epidermal growth factor receptor (EGFR) and CDKN2A alterations and determine the prognostic significance of EGFR and CDKN2A alterations on regulated genes in patients with glioblastoma (GBM) or lower grade glioma (LGG).Methods: The alteration frequencies of EGFR and CDKN2A across 32 tumor types were derived from cBioPortal based on The Cancer Genome Atlas (TCGA) datasets. The Kaplan–Meier analysis was used to determine the prognostic significance of EGFR and CDKN2A alterations. EGFR and CDKN2A alterations on regulated expression signatures were identified from RNA-seq data in the TCGA GBM datasets. The prognostic significance of EGFR and CDKN2A alterations on regulated genes in patients with glioma was determined using the TCGA and the Chinese Glioma Genome Atlas (CGGA) datasets.Results: Compared with the other 31 tumor types, EGFR amplification and CDKN2A deletion particularly occurred in patients with GBM. GBM patients with EGFR amplification or CDKN2A deletion demonstrated poor prognosis. Statistical analysis showed the coexistence of EGFR alteration and CDKN2A deletion in GBM patients. We identified 864 genes which were commonly regulated by EGFR amplification and CDKN2A deletion, and those genes were highly expressed in brain tissues and associated with the cell cycle, EBRR2, and MAPK signaling pathways. Spermatogenesis-associated serine-rich 2-like gene (SPATS2L) was upregulated in GBM patients with EGFR amplification or CDKN2A alteration. Higher expression levels of SPATS2L were associated with worse prognosis in patients with GBM in both TCGA and CGGA datasets. Moreover, the expression levels of SPATS2L were higher in patients with a mesenchymal subtype of GBM. Statistical analysis also showed that the coexistence of EGFR alteration and CDKN2A deletion was significant in patients with LGG. SPATS2L was upregulated in LGG patients with EGFR amplification or CDKN2A alteration. Furthermore, higher expression levels of SPATS2L were associated with worse prognosis in patients with LGG in both TCGA and CGGA datasets. The expression levels of SPATS2L were higher in patients with an astrocytoma subtype of LGG. Finally, the coexistence and unfavorable prognostic effects of EGFR amplification and CDKN2A alteration were validated using the Memorial Sloan Kettering Cancer Center (MSKCC) glioma datasets.Conclusions: EGFR amplification and CDKN2A deletion of the regulated gene SPATS2L have significant prognostic effects in patients with GBM or LGG.

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Oncogenic DIRAS3 promotes malignant phenotypes of glioma by activating EGFR-AKT signaling

Cited by 9 publications

References 16 publications

A risk signature with four autophagy‐related genes for predicting survival of glioblastoma multiforme

A risk signature with four autophagy‐related genes for predicting survival of glioblastoma multiforme

Frequent Epigenetic Inactivation of DIRAS-1 and DIRAS-2 Contributes to Chemo-Resistance in Gliomas

Analysis of the EGFR Amplification and CDKN2A Deletion Regulated Transcriptomic Signatures Reveals the Prognostic Significance of SPATS2L in Patients With Glioma

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