Tbx2 confers poor prognosis in glioblastoma and promotes temozolomide resistance with change of mitochondrial dynamics

Yi, Fuxin; Du, Jianzhou; Ni, Wenjie; Liu, Weixian

doi:10.2147/ott.s124012

Cited by 12 publications

(14 citation statements)

References 26 publications

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“…DEG analysis also included increased expression of SLC6A1, SLC6A11, and GABBR2 in VWM, which encode major transmembrane γ-aminobutyric acid (GABA) transporters GAT-1, GAT-3, and GABAb receptor subunit 2, respectively. 38 In contrast to the protective effect of TBX2, our VWM human WM astrocytes also showed a decreased expression of MT2A, an antioxidative, anti-inflammatory, and antiapoptotic metallothionein secreted by astrocytes that is well known for its neuroprotective properties. This may further lead to astrocytic glutamate release, thereby potentiating inhibitory synaptic transmission, and to astrocytic ATP/adenosine-mediated heterosynaptic suppression affecting excitatory transmission.…”

Section: Discussionmentioning

confidence: 64%

“…In astrocytoma cell lines, TBX2 has been shown to promote proliferation, to inhibit cleaved caspase 3-mediated apoptosis by stimulating mitochondrial fission, and to increase mitochondrial DNA content. 38 In contrast to the protective effect of TBX2, our VWM human WM astrocytes also showed a decreased expression of MT2A, an antioxidative, anti-inflammatory, and antiapoptotic metallothionein secreted by astrocytes that is well known for its neuroprotective properties. 39 Mitochondrial mechanisms involved in VWM pathophysiology corroborate recent findings in primary astrocytes of Eif2b5 R132H/R132H mice indicating that an impaired oxidative phosphorylation in these cells is compensated by increased mitochondrial content and glycolysis.…”

Section: Discussionmentioning

confidence: 64%

“…TBX2 was also upregulated in VWM human WM astrocytes. In astrocytoma cell lines, TBX2 has been shown to promote proliferation, to inhibit cleaved caspase 3–mediated apoptosis by stimulating mitochondrial fission, and to increase mitochondrial DNA content . In contrast to the protective effect of TBX2 , our VWM human WM astrocytes also showed a decreased expression of MT2A , an antioxidative, anti‐inflammatory, and antiapoptotic metallothionein secreted by astrocytes that is well known for its neuroprotective properties .…”

Section: Discussionmentioning

confidence: 81%

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Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter

Leferink

Dooves

Hillen

et al. 2019

Annals of Neurology

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Objective: Astrocytes have gained attention as important players in neurological disease. In line with their heterogeneous character, defects in specific astrocyte subtypes have been identified. Leukodystrophy vanishing white matter (VWM) shows selective vulnerability in white matter astrocytes, but the underlying mechanisms remain unclear. Induced pluripotent stem cell technology is being extensively explored in studies of pathophysiology and regenerative medicine. However, models for distinct astrocyte subtypes for VWM are lacking, thereby hampering identification of disease-specific pathways. Methods: Here, we characterize human and mouse pluripotent stem cell-derived gray and white matter astrocyte subtypes to generate an in vitro VWM model. We examined morphology and functionality, and used coculture methods, high-content microscopy, and RNA sequencing to study VWM cultures. Results: We found intrinsic vulnerability in specific astrocyte subpopulations in VWM. When comparing VWM and control cultures, white matter-like astrocytes inhibited oligodendrocyte maturation, and showed affected pathways in both human and mouse cultures, involving the immune system and extracellular matrix. Interestingly, human white matter-like astrocytes presented additional, human-specific disease mechanisms, such as neuronal and mitochondrial functioning. Interpretation: Astrocyte subtype cultures revealed disease-specific pathways in VWM. Cross-validation of human-and mouse-derived protocols identified human-specific disease aspects. This study provides new insights into VWM disease mechanisms, which helps the development of in vivo regenerative applications, and we further present strategies to study astrocyte subtype vulnerability in neurological disease.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 81%

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Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter

Leferink

Dooves

Hillen

et al. 2019

Annals of Neurology

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“…We found that most of those probes identified in 7 cancers are located in non-island regions. Moreover, some genes of those CpG sites located have been reported to be associated with the prognosis of various cancers (such as SHANK2 [31], LTBP1 [32], GRIA4 [33], OSR2 [33], PHLDB2 [34], TBX2 [35][36][37] and GPR37 [38]). Currently, no qualified independent dataset is available for systematically estimating the reproducibility and validity of the probe-based prognostic classifier, thus a further verification of this prognostic model would be necessary in the future.…”

Section: Prognostic Model Successfully Divides Patients Into High-rismentioning

confidence: 99%

Integrative analysis identifies potential DNA methylation biomarkers for pan-cancer diagnosis and prognosis

2019

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DNA methylation status is closely associated with diverse diseases, and is generally more stable than gene expression, thus abnormal DNA methylation could be important biomarkers for tumor diagnosis, treatment and prognosis. However, the signatures regarding DNA methylation changes for pan-cancer diagnosis and prognosis are less explored. Here we systematically analyzed the genome-wide DNA methylation patterns in diverse TCGA cancers with machine learning. We identified seven CpG sites that could effectively discriminate tumor samples from adjacent normal tissue samples for 12 main cancers of TCGA (1216 samples, AUC > 0.99). Those seven potential diagnostic biomarkers were further validated in the other 9 different TCGA cancers and 4 independent datasets (AUC > 0.92). Three out of the seven CpG sites were correlated with cell division, DNA replication and cell cycle. We also identified 12 CpG sites that can effectively distinguish 26 different cancers (7605 samples), and the result was repeatable in independent datasets as well as two disparate tumors with metastases (micro-average AUC > 0.89). Furthermore, a series of potential signatures that could significantly predict the prognosis of tumor patients for 7 different cancer were identified via survival analysis (p-value < 1e-4). Collectively, DNA methylation patterns vary greatly between tumor and adjacent normal tissues, as well as among different types of cancers. Our identified signatures may aid the decision of clinical diagnosis and prognosis for pan-cancer and the potential cancer-specific biomarkers could be used to predict the primary site of metastatic breast and prostate cancers.

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“…As noted above, both pathological and clinical studies have shown that higher DRP1 expression is correlated with worse prognosis in patients concurrently treated with TMZ and irradiation [43,44].…”

Section: Silencing Of Drp1 Expression In Gbm Cells Decreases Cell Gromentioning

confidence: 74%

Higher Levels of Dynamin-related Protein 1 are Associated with Reduced Radiation Sensitivity of Glioblastoma Cells

Cheng

Chow

Chiao

et al. 2020

CNR

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Background: Dynamin-related protein 1 (DRP1) is a GTPase involved in mitochondrial fission, mitochondrial protein import, and drug sensitivity, suggesting an association with cancer progression. This study was conducted to evaluate the prognostic significance of DRP1 in glioblastoma multiforme (GBM). Methods: DRP1 expression was measured by immunohistochemistry and Western blotting. Correlations between DRP1 expression and clinicopathological parameters were determined by statistical analysis. Differences in survival were compared using the log-rank test. DRP1 expression was detected in 87.2% (41/47) of the investigated patients with GBM. Results: The patients with higher DRP1 levels had worse survival (p = 0.0398). In vitro, the silencing of DRP1 reduced cell proliferation, invasive potential, and radiation resistance. The addition of shikonin inhibited DRP1 expression and increased drug uptake. Moreover, shikonin reduced the nuclear entry of DNA repair-associated enzymes and increased radiation sensitivity, suggesting that reducing DRP1 expression could inhibit DNA repair and increase the radiation sensitivity of GBM cells. Conclusion: Our results indicate that DRP1 overexpression is a prospective radio-resistant phenotype in GBM. Therefore, DRP1 could be a potential target for improving the effectiveness of radiation therapy.

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Tbx2 confers poor prognosis in glioblastoma and promotes temozolomide resistance with change of mitochondrial dynamics

Cited by 12 publications

References 26 publications

Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter

Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter

Integrative analysis identifies potential DNA methylation biomarkers for pan-cancer diagnosis and prognosis

Higher Levels of Dynamin-related Protein 1 are Associated with Reduced Radiation Sensitivity of Glioblastoma Cells

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