GQIcombi application to subdue glioma via differentiation therapy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1054628 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27288905.fastq.gz | Fastqsanger.gz | |||
| SRR27288906.fastq.gz | Fastqsanger.gz | |||
| SRR27288907.fastq.gz | Fastqsanger.gz | |||
| SRR27288908.fastq.gz | Fastqsanger.gz |
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Project description:Modern therapy approaches fail to prevent high grade glioma recurrence. So, alternative ways need to be developed. Changing glioma cells’ fate is an alternative way to prevent tumor growth. Two-step protocol based on an antiproliferative G-quadruplex and small molecules triggering neural differentiation showed to be effective on glioblastoma cell cultures. This approach was named a differential therapy. In this paper, we broaden the spectrum of cell cultures to gliomas of II, III and IV grades, showing the universality of suggested protocol on a variety of cancer cells. We checked the reasonability of consistent addition of factors to the glioma cells. Moreover, we demonstrated a significant inhibition of tumor growth after injection of GQIcombi into 101/8 tumor in glioma rat model. Thus, the proposed strategy of influencing on cancer cell growth is applicable to be further translated for therapy use.
2024-01-09 | GSE250617 | GEO
Project description:Current therapy protocols fail to cure high-grade gliomas and prevent recurrence. Therefore, novel approaches need to be developed. A re-programing of glioma cell fate is an alternative attractive way to stop tumor growth. The two-step protocol applies the antiproliferative GQ bi-(AID-1-T) and small molecule inducers with BDNF to trigger neural differentiation into terminally differentiated cells, and it is very effective on GB cell cultures. This original approach is a successful example of the "differentiation therapy". To demonstrate a versatility of this approach, in this publication we have extended a palette of cell cultures to gliomas of II, III and IV Grades, and proved an applicability of that version of differential therapy for a variety of tumor cells. We have justified a sequential mode of adding of GQIcombi components to the glioma cells. We have shown a significant retardation of tumor growth after a direct injection of GQIcombi into the tumor in rat brain, model 101/8. Thus, the proposed strategy of influencing on cancer cell growth is applicable to be further translated for therapy use.
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Project description:Glioma initiating/stem cells (GIC/GSC) are considered responsible for the therapeutic resistance and recurrence of malignant glioma. To clarify the molecular mechanism of GIC/GSC maintenance/differentiation, we established GIC/GSC clones, having the potential to differentiate into malignant gliomas, from glioblastoma patient’s tissues, and subjected to DNA microarray/iTRAQ based integrated proteomics. 21,857 mRNAs and 8,471 proteins were identified and integrated into a gene/protein expression analysis chart (iPEACH). The data integration and extraction of global proteins and mRNAs revealed that, during the GIC/GSC differentiation, cell adhesion molecules including integrin aV/ECMs and RAS-MAPK/PI3K signalings were significantly up-regulated, meanwhile, SOX2, CD133, and specific proteoglycans/synthetic-enzymes/metabolic pathways were obviously down-regulated. Among them, we focused proteoglycans and their synthetic-enzymes. GIC/GSC differentiation was significantly associated with the decrease of CSPG (CS-modified form) and dramatically induced by the CS-degradation enzyme which also induces the up-regulation of ERK-AKT signaling and GFAP without any other agents. Importantly, these differentiation processes were also associated with the interaction of CSPG (CS-unmodified form) and integrin-aV, and suppressed by integrin-inhibitors/CS administrations significantly. Combination treatments of a cancer-drug Temozolomide and these GIC/GSC-differentiation inhibitors suppressed glioma progression, increased the chemosensitivities, and led the longer survival of mouse xenograft-models. Functional integrated proteomics for the first time demonstrates that the GIC/GSC induces the specific proteoglycans to regulate GIC/GSC stemness/differentiation via the integlin signalings which may be a clinical target against malignant gliomas.
2018-11-30 | PXD008331 | JPOST Repository
Project description:Glioma initiating/stem cells (GIC/GSC) are considered responsible for the therapeutic resistance and recurrence of malignant glioma. To clarify the molecular mechanism of GIC/GSC maintenance/differentiation, we established GIC/GSC clones, having the potential to differentiate into malignant gliomas, from glioblastoma patient’s tissues, and subjected to DNA microarray/iTRAQ based integrated proteomics. 21,857 mRNAs and 8,471 proteins were identified and integrated into a gene/protein expression analysis chart (iPEACH). The data integration and extraction of global proteins and mRNAs revealed that, during the GIC/GSC differentiation, cell adhesion molecules including integrin aV/ECMs and RAS-MAPK/PI3K signalings were significantly up-regulated, meanwhile, SOX2, CD133, and specific proteoglycans/synthetic-enzymes/metabolic pathways were obviously down-regulated. Among them, we focused proteoglycans and their synthetic-enzymes. GIC/GSC differentiation was significantly associated with the decrease of CSPG (CS-modified form) and dramatically induced by the CS-degradation enzyme which also induces the up-regulation of ERK-AKT signaling and GFAP without any other agents. Importantly, these differentiation processes were also associated with the interaction of CSPG (CS-unmodified form) and integrin-aV, and suppressed by integrin-inhibitors/CS administrations significantly. Combination treatments of a cancer-drug Temozolomide and these GIC/GSC-differentiation inhibitors suppressed glioma progression, increased the chemosensitivities, and led the longer survival of mouse xenograft-models. Functional integrated proteomics for the first time demonstrates that the GIC/GSC induces the specific proteoglycans to regulate GIC/GSC stemness/differentiation via the integlin signalings which may be a clinical target against malignant gliomas.
2018-11-30 | PXD008332 | JPOST Repository
Project description:<p><strong>INTRODUCTION:</strong> Neuronal activity regulated by synaptic communication exerts an important role in tumorigenesis and progression in brain tumors. Genes for soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) annotated with the function ‘vesicle’ about synaptic connectivity were identified and one of these proteins, synaptosomal-associated protein 25 (SNAP25), was found to have discrepant expression levels in neuropathies. However, the specific mechanism and prognostic value of SNAP25 during glioma progression remain unclear. </p><p><strong>METHODS:</strong> Using RNA sequencing data from The Cancer Genome Atlas (TCGA) database, the differential synaptosis-related genes between LGG and GBM were identified as highly correlated. Cox proportional hazards regression analysis and survival analysis indicated that the candidate gene SNAP25 could differentiate the outcome of low- and high-risk patients, and the Chinese Glioma Genome Atlas (CGGA) cohort was used for validation of the data set. RT-qPCR, western blot, and immunohistochemistry assays were performed to examine the expression level of SNAP25 in glioma cells and samples. Functional assays were performed to identify the effects of SNAP25 knockdown and overexpression on cell viability, migration, and invasion. Then, an immunofluorescence assay of the xenograft tissue was applied to evaluate the expression of the neuronal dendron formation marker-MAP2. Liquid chromatography-high re solution mass spectrometry (LC-MS)-based metabolomics approach was presented for identifying crucial metabolic disturbances in glioma cells. In situ mouse xenograft model was used to investigate the role of SNAP25 in vivo.</p><p><strong>RESULTS:</strong> SNAP25 was down expressed in glioma tissues and cell lines and low-level SNAP25 indicated an unfavorable prognosis of glioma patients. SNAP25 inhibited cell proliferation, migration, invasion and fostered glutamate metabolism of glioma cells, exerting a tumor suppressor role. SNAP25 overexpression expressed lower expression of MAP2, indicating poor neuronal plasticity and connectivity. SNAP25 could interact with glutaminase（GLS）and GLS knockdown could rescue the anti-tumor effect of SNAP25 in glioma cells. Moreover, upregulation of SNAP25 also decreased tumor volume and prolonged the overall survival (OS) of the xenograft mouse.</p><p><strong>CONCLUSION:</strong> SNAP25 inhibited carcinogenesis of glioma via sponging glutamate metabolism by regulating GLS expression, as well as inhibiting dendritic formation, which could be considered as a molecular target for glioma diagnosis and therapy.</p>
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Project description:A hallmark feature of glioblastoma (GBM) cells is its strong self-renewal potential and immature differentiation state -- stem cell-like properties which may contribute to the plasticity and intense therapeutic resistance of GBM. The molecular basis of the immature differentiation profile remains an area of active investigation. Here, integrated genomic and biological analyses identified PLAGL2 as a potent proto-oncogene targeted for amplification/gain in malignant gliomas as well as in colorectal cancers. High level of PLAGL2 expression strongly suppresses neural stem cell (NSC) and glioma-initiating cell (GIC) differentiation while promoting their proliferation and self-renewal capacity under differentiation induction conditions. On the mechanistic level, the PLAGL2 transcriptome analysis revealed that these differentiation suppressive activities are attributable in part to PLAGL2 modulation of Wnt/beta-catenin signaling via up-regulation of Wnt6 ligand as well as Fzd9 and Fzd2 receptor expression. Correspondingly, inhibition of Wnt signaling in PLAGL2-expressing NSC partially restores their differentiation capacity. The identification of PLAGL2 as a glioma oncogene highlights the importance of a growing class of cancer genes functioning to impart stem cell-like characteristics on malignant cells. p53-null mouse NSCs are infected with retrovirus expressing either control vector or PlagL2. Total RNA were collected upon differentiation in 1% FBS for 24 hr. 3 replicates each.
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