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1.
Neurol India ; 69(4): 1005-1009, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34507430

RESUMO

Background: Gliomas are aggressive tumors with limited treatment options. Immunotherapy targets are under evaluation as new therapeutic targets in gliomas. Aims and Objectives: The aims of the study were to analyze expression of PDL1 in adult diffuse gliomas in World Health Organization grade II, III, and IV and to corelate its expression with demographic features, IDH-1, ATRX, and p-53 mutation status. Materials and Methods: This was a case series that included 30 cases of adult diffuse glioma. In all cases, a composite diagnosis including histologic type, grade, and molecular alterations was rendered. PDL1 testing was done by immunohistochemistry using PDL1 SP-263 antibody. Results: PDL1 expression was identified in 33.3% cases in tumor cells and in 6.67% cases in immune cells. All neoplasms with PDL1 expression were astrocytic tumors. PDL1 expression was significantly associated with IDH-1 immunonegative gliomas (P = 0.013). Conclusion: PDL1 is a novel therapeutic target in gliomas. The current study is an attempt to evaluate the expression of PDL1 over the varied spectrum of gliomas.


Assuntos
Neoplasias Encefálicas , Glioma , Antígeno B7-H1/genética , Neoplasias Encefálicas/genética , Glioma/genética , Humanos , Isocitrato Desidrogenase/genética , Mutação
2.
J Transl Med ; 19(1): 352, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404444

RESUMO

BACKGROUND: As an important part of tumor immunotherapy for adjunct, therapeutic tumor vaccines have been effective against multiple solid cancers, while their efficacy against lower grade glioma (LGG) remains undefined. Immunophenotyping of tumors is an essential tool to evaluate the immune function of patients with immunodeficiency or autoimmunity. Therefore, this study aims to find the potential tumor antigen of LGG and identify the suitable population for cancer vaccination based on the immune landscape. METHOD: The genomic and clinical data of 529 patients with LGG were obtained from TCGA, the mRNA_seq data of normal brain tissue were downloaded from GTEx. Differential expression gene and mutation analysis were performed to screen out potential antigens, K-M curves were carried out to investigate the correlation between the level of potential antigens and OS and DFS of patients. TIMER dataset was used to explore the correlation between genes and immune infiltrating cells. Immunophenotyping of 529 tumor samples was based on the single-sample gene sets enrichment analysis. Cibersort and Estimate algorithm were used to explore the tumor immune microenvironment characteristics in each immune subtype. Weighted gene co-expression network analysis (WGCNA) clustered immune-related genes and screened the hub genes, and pathway enrichment analyses were performed on the hub modules related to immune subtype in the WGCNA. RESULTS: Selecting for the mutated, up-regulated, prognosis- and immune-related genes, four potential tumor antigens were identified in LGG. They were also significantly positively associated with the antigen-presenting immune cells (APCs). Three robust immune subtypes, IS1, IS2 and IS3, represented immune status "desert", "immune inhibition", and "inflamed" respectively, which might serve as a predictive parameter. Subsequently, clinicopathological features, including the codeletion status of 1p19q, IDH mutation status, tumor mutation burden, tumor stemness, etc., were significantly different among subtypes. CONCLUSION: FCGBP, FLNC, TLR7, and CSF2RA were potential antigens for developing cancer vaccination, and the patients in IS3 were considered the most suitable for vaccination in LGG.


Assuntos
Neoplasias Encefálicas , Glioma , Vacinas , Antígenos de Neoplasias/genética , Neoplasias Encefálicas/genética , Glioma/genética , Humanos , RNA Mensageiro/genética , Microambiente Tumoral
3.
Zhonghua Bing Li Xue Za Zhi ; 50(7): 734-739, 2021 Jul 08.
Artigo em Chinês | MEDLINE | ID: mdl-34405606

RESUMO

Objective: To analyze the clinicopathological and molecular features and prognostic implications of adult isocitrate dehydrogenase wild type (IDH-wt) diffuse gliomas. Methods: A total of 87 cases of adult IDH-wt diffuse gliomas from 2016 to 2020 in Xuanwu Hospital of Capital Medical University were retrospectively collected. The clinicopathological characteristics and prognosis were analyzed. Molecular characteristics were also analyzed using Sanger sequencing and next generation sequencing. Results: There were 53 males and 34 females, aged from 19 to 78 years (mean 53 years). Histopathologically, there were 63 (72.4%) glioblastomas, 16 (18.4%) anaplastic astrocytomas, six (6.9%) diffuse astrocytomas, and one (1.1%) each of anaplastic oligodendrocytoma, and anaplastic oligodendroglioma. Common molecular genetic changes in IDH-wt gliomas included TERT promoter mutation which was found in 60 cases (69.0%); MGMT promoter methylation in 43 cases (49.4%); EGFR mutation in 38 cases (43.7%); PTEN mutation in 35 cases (40.2%) and TP53 mutation in 32 cases (36.8%). In addition, PDGFRA mutation was detected in 17 cases (19.5%), CDK4 amplification in 15 cases (17.2%) and MDM2 amplification in 11 cases (12.6%). In IDH-wt diffuse gliomas, there was no significant difference in the overall survival between TERT promoter, EGFR, PTEN, TP53, PDGFRA, CDK4, MDM2 mutations and the wild-type, since these gene mutations could co-occur in any case (P>0.05). Also there was no significant difference in the overall survival between the WHO grade Ⅱ/Ⅲ gliomas and glioblastoma patients with these gene mutations (P>0.05). Conclusions: TERT promoter, EGFR, PTEN, TP53, PDGFRA, CDK4 and MDM2 gene mutations are common molecular genetic changes in adult IDH-wt gliomas, and are associated with poor prognosis. It is suggested that these genes are potentially useful for predicting the prognosis and should be tested in adult IDH-wt gliomas.


Assuntos
Neoplasias Encefálicas , Glioma , Telomerase , Adulto , Neoplasias Encefálicas/genética , Feminino , Glioma/genética , Humanos , Isocitrato Desidrogenase/genética , Masculino , Biologia Molecular , Mutação , Prognóstico , Estudos Retrospectivos , Telomerase/genética
5.
Zhonghua Bing Li Xue Za Zhi ; 50(8): 865-869, 2021 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-34344068

RESUMO

Objective: To analyze the clinicopathological features of chordoid glioma. Methods: A total of 12 cases of chordoid gliomas from 2009 to 2020 in Xuanwu Hospital of Capital Medical University and General Hospital of Chinese People's Liberation Army were retrospectively analyzed. The clinical and imaging characteristics, pathologic and molecular characteristics were analyzed, and the relevant literature was reviewed. Results: All 12 patients (4 males and 8 females) aged from 25 to 67 years (mean 39 years) and mainly had a history of headache or/and vision loss. MRI showed that the lesions located in the third ventricle, and they showed abnormal enhancement. Pathologically, these 12 cases displayed the morphologic characteristics of chordoid gliomas, including papillary structures in two cases. Immunohistochemically, GFAP and vimentin were expressed in all 12 cases (12/12). TTF1 was also expressed in all cases (10/10). CD34 and CKpan were seen in 11 cases (11/12). EMA with dot-and/or-ring like positivity was seen in 9 cases (9/10). Tissues were available in nine chordoid gliomas for Sanger sequencing to detect PRKCA and IDH gene mutation, and eight cases (8/9) showed PRKCA gene D463H mutation. None of these cases showed IDH1 R132 and IDH2 R172 mutation. All 12 patients underwent surgery, and four were lost to follow up. The remaining eight patients were progression or recurrence free at last follow-up in January 2021. Conclusions: Chordoid gliomas have relatively distinguishing clinical and histopathological features. PRKCA gene mutation in chordoid gliomas can be considered as a biomarker for the diagnosis and differential diagnosis of chordoid gliomas, and may provide a direction for future targeted therapy.


Assuntos
Neoplasias do Ventrículo Cerebral , Glioma , Terceiro Ventrículo , Feminino , Glioma/diagnóstico por imagem , Glioma/genética , Humanos , Masculino , Estudos Retrospectivos , Vimentina/genética
6.
No Shinkei Geka ; 49(4): 901-908, 2021 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-34376622

RESUMO

BACKGROUND: Diffuse midline glioma, H3K27M mutant is a glioma located in the thalamus, brainstem, or spine with the H3K27M mutation, which is a new entity in the 2016 revised WHO classification. The treatment of thalamic glioma(TG)and brainstem glioma(BSG), which includes diffuse midline gliomas, the H3K27M mutant is challenging, and there are no standard therapeutic strategies. It is important to determine the characteristics of these brain tumors. Here, we retrospectively reviewed 31 consecutive patients with TG and BSG who were treated at our institute between January 1994 and May 2018, including methionine-positron emission tomography(MET-PET)data. RESULTS: Fourteen patients had TG, while 17 patients had BSG. Six patients were children, and 25 were adults. Nine patients with TGs and seven with BSG were enhanced by gadolinium. Twenty-seven patients were treated with radiotherapy, and 20 patients were treated with chemotherapy. All 21 tumors that underwent surgery showed wild-type IDH. The H3K27M mutation was present in four TG and two BSG. There was no statistically significant association between methionine uptake and gadolinium contrast enhancement and tumor grade. The median overall survival period(OS)of all cases was 16.9 months, whereas those of TG and BSG were 22.8 and 10.0 months, respectively. CONCLUSION: Because TG and BSG still have poor prognoses, it is necessary to elucidate the pathology of the disease and establish its standard therapy.


Assuntos
Neoplasias Encefálicas , Glioma , Adulto , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Tronco Encefálico , Criança , Glioma/diagnóstico por imagem , Glioma/genética , Glioma/terapia , Histonas/genética , Humanos , Mutação , Estudos Retrospectivos , Tálamo/diagnóstico por imagem
9.
Gen Physiol Biophys ; 40(4): 257-274, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34350832

RESUMO

Autophagy may provide the source of nutrients for tumor cells. We aim to develop an autophagy-related signature to predict the progression from lower-grade gliomas (LGG) to glioblastoma multiforme (GBM) and prognosis. Totally, 686 differentially expressed genes (DEGs) and 73 long non-coding RNAs (DELs) were identified between GBM and LGG samples from the Chinese Glioma Genome Atlas (CGGA). Of them, 131 DEGs were intersected with autophagy genes from the Human Autophagy Database; while 54 DELs co-expressed with autophagy-related DEGs. Ten autophagy-related genes were associated with overall survival and could distinguish GBM from LGG, with the accuracy of 0.891 using CGGA dataset and 0.790 using The Cancer Genome Atlas (TCGA) dataset. The risk score was established based on these 10 genes. Patients with higher risk score were at an increased risk of developing GBM (49.7% vs. 21.3%; p < 0.001) and worse prognosis than those in low risk group. The prognostic accuracy was 0.840 and 0.744 for CGGA and TCGA dataset, respectively. Age, recurrence, isocitrate dehydrogenase mutation and risk score were independent prognostic factors and thus they were used to build a nomogram which showed the highest prognostic power. This established nomogram may aid the clinical decision making of personalized treatment..


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , RNA Longo não Codificante , Autofagia/genética , Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/diagnóstico , Glioblastoma/genética , Glioma/diagnóstico , Glioma/genética , Humanos , RNA Mensageiro
10.
Viruses ; 13(7)2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34372567

RESUMO

Glioblastoma is the most malignant and most common form of brain tumor, still today associated with a poor 14-months median survival from diagnosis. Protein kinase A, particularly its regulatory subunit R2Alpha, presents a typical intracellular distribution in glioblastoma cells compared to the healthy brain parenchyma and this peculiarity might be exploited in a therapeutic setting. In the present study, a third-generation lentiviral system for delivery of shRNA targeting the regulatory subunit R2Alpha of protein kinase A was developed. Generated lentiviral vectors are able to induce an efficient and stable downregulation of R2Alpha in different cellular models, including non-stem and stem-like glioblastoma cells. In addition, our data suggest a potential correlation between silencing of the regulatory subunit of protein kinase A and reduced viability of tumor cells, apparently due to a reduction in replication rate. Thus, our findings support the role of protein kinase A as a promising target for novel anti-glioma therapies.


Assuntos
Subunidade RIIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Subunidade RIIalfa da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Glioblastoma/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Subunidade RIIalfa da Proteína Quinase Dependente de AMP Cíclico/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Glioblastoma/genética , Glioblastoma/fisiopatologia , Glioma/genética , Glioma/metabolismo , Células HEK293 , Humanos , Lentivirus/genética , Interferência de RNA , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Transdução Genética/métodos
11.
Molecules ; 26(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34443374

RESUMO

The activation of NFAT (nuclear factor of activated T cells) transcription factors by calcium-dependent phosphatase calcineurin is a key step in controlling T cell activation and plays a vital role during carcinogenesis. NFATs are overexpressed in many cancers, including the most common primary brain tumor, gliomas. In the present study, we demonstrate the expression of NFATs and NFAT-driven transcription in several human glioma cells. We used a VIVIT peptide for interference in calcineurin binding to NFAT via a conserved PxIxIT motif. VIVIT was expressed as a fusion protein with a green fluorescent protein (VIVIT-GFP) or conjugated to cell-penetrating peptides (CPP), Sim-2 or 11R. We analyzed the NFAT expression, phosphorylation, subcellular localization and their transcriptional activity in cells treated with peptides. Overexpression of VIVIT-GFP decreased the NFAT-driven activity and inhibited the transcription of endogenous NFAT-target genes. These effects were not reproduced with synthetic peptides: Sim2-VIVIT did not show any activity, and 11R-VIVIT did not inhibit NFAT signaling in glioma cells. The presence of two calcineurin docking sites in NFATc3 might require dual-specificity blocking peptides. The cell-penetrating peptides Sim-2 or 11R linked to VIVIT did not improve its action making it unsuitable for evaluating NFAT dependent events in glioma cells with high expression of NFATc3.


Assuntos
Neoplasias Encefálicas/patologia , Calcineurina/metabolismo , Glioma/patologia , Fatores de Transcrição NFATC/metabolismo , Oligopeptídeos/farmacologia , Transdução de Sinais , Sequência de Aminoácidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Peptídeos Penetradores de Células/farmacologia , Glioma/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Fatores de Transcrição NFATC/química , Oligopeptídeos/química , Peptídeos/farmacologia , Transporte Proteico/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos
12.
J Transl Med ; 19(1): 335, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362400

RESUMO

BACKGROUND: Glioma is the most common primary brain tumor and represents one of the most aggressive and lethal types of human cancer. BCL7 family has been found in several cancer types and could be involved in tumor progression. While the role of BCL7 family in human glioma has remained to be elucidated. METHODS: Paraffin-embedded tumor samples were obtained to detect BCL7 expression by performing in glioma. Data (including normalized gene expression and corresponding clinical data) were obtained from Gliovis, CGGA, GEO, cBioportal and Oncomine and were used to investigate BCL7 genes expression in glioma. Survival analyses were calculated by Kaplan-Meier methods and Cox regression analysis in TCGA and CGGA. Gene Set Enrichment Analyses (GSEA) and gene ontology (GO) analysis was employed to perform the biological processes enrichment. RESULTS: BCL7A expression in glioma tissues was lower compared to non-tumor brain tissues (NBT), and exhibited a negative correlation with glioma grades. Results from immunohistochemical (IHC) staining and public dataset validation demonstrated that BCL7B and BCL7C were highly expressed in glioma tissues compared to NBT. Cox regression analysis identified BCL7A as the only gene in the BCL7 family that was independently associated with the prognosis of lower-grade glioma (LGG) and glioblastoma (GBM). GO and GSEA analyses revealed the potential contribution of BCL7A in adaptive immune response and neutrophil activation in the tumor microenvironment. Moreover, we found that BCL7A had no prognostic effect on the overall survival of GBM patients who received IR only; however, patients who received chemotherapy (TMZ) combined with IR in the high BCL7A group survived longer than patients in the low BCL7A group (HR = 0.346, p < 0.05). CONCLUSION: BCL7A is a new tumor suppressor gene and can be adopted as a biomarker for independent prognosis in glioma and to evaluate response to TMZ.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioma/genética , Humanos , Proteínas dos Microfilamentos , Proteínas Oncogênicas , Prognóstico , Microambiente Tumoral
13.
J Transl Med ; 19(1): 338, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34372858

RESUMO

BACKGROUND: Fine tuned balance of reactive oxygen species (ROS) is essential for tumor cells and tumor cells use immune checkpoints to evade attack form immunity system. However, it's unclear whether there is any crosstalk between these two pathways. CYB561D2, an antioxidant protein, is part of 5-gene prognosis signature in gliomas and its involvement in gliomas is unknown. Here, we aim to provide a detailed characterization of CYB561D2 in gliomas. METHODS: CYB561D2 expression was measured in clinical samples of gilomas and normal tissues. The effects of CYB561D2 on immunity related genes and tumor behaviors were investigated in glioma cell lines with various in vitro and in vivo assays. RESULTS: CYB561D2 expression was enhanced in gliomas compared to control tissues. CYB561D2 up-regulation was associated with high grading of gliomas and short survival in patients. CYB561D2 expression was induced by H2O2 in glioma cell lines. CYB561D2 and its functional product ascorbate activated STAT3 dose-dependently. CYB561D2 over-expression increased PD-L1, CCL2 and TDO2 expression, and induced immunosuppression in co-cultured T cells. In in vitro assays, CYB561D2 knock-down suppressed cell growth, colony formation, migration and promoted apoptosis. In contrast, CYB561D2 over-expression reduced survival rate in intracranial glioma model and this effect could be blocked by dominant negative-STAT3. The CYB561D2 up-regulation and the positive association of CYB561D2 with PD-L1, CCL2 and TDO2 expression were cross-validated in open-access datasets. CONCLUSIONS: CYB561D2 up-regulation induces immunosuppression and aggression via activating STAT3 in gliomas and CYB561D2 mediates ROS-tumor immunity crosstalk.


Assuntos
Neoplasias Encefálicas , Glioma , Agressão , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Humanos , Peróxido de Hidrogênio , Imunossupressão , Fator de Transcrição STAT3/metabolismo , Regulação para Cima/genética
14.
Medicine (Baltimore) ; 100(33): e26921, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34414948

RESUMO

BACKGROUND: The molecular mechanism of Glioma is still unclear, and there are few early diagnostic markers. Therefore, it is urgent to figure out effective preventive measures, active diagnostic methods and rapid treatment measures. In recent years, relevant studies have revealed that long non-coding RNA (lncRNA) is associated with the prognosis of Glioma. However, these results have not been supported by any evidence. Therefore, this study carried out a meta-analysis method to analyze the relationship between lncRNA and the prognosis of Glioma. In addition, bioinformatics analysis was conducted to investigate the mechanism and related pathways of lncRNAs in Glioma. METHODS: We performed a systematic search in electronic databases, including China National Knowledge Infrastructure, Chinese Biomedical literature Database, Chinese Scientific and Journal Database, Wan Fang database, PubMed, EMBASE, Cochrane Library and Web of Science, to investigate the potential association between lncRNA expression and prognostic significance and clinical features in glioma patients. Hazards ratios (HRs) with corresponding 95% confidence intervals (CIs) were pooled to estimate the prognosis value of lncRNA by Stata16.0 software. The online tool AnnoLnc was applied to screen the co-expressed gene related to each lncRNA, David was used for gene ontology (GO) analysis and enrichment analysis of the signal pathway, and through Starbase, the possible competitive endogenous RNA network of lncRNAs was constructed. RESULTS: The results of this meta-analysis would be submitted to peer-reviewed journals for publication. CONCLUSION: This study will provide evidence-based medical evidence for lncRNA, so as to predict the prognosis of Glioma and bioinformatics analysis will provide ideas for the mechanism study on Glioma.


Assuntos
Biomarcadores Tumorais/genética , Glioma/genética , Metanálise como Assunto , RNA Longo não Codificante/genética , Projetos de Pesquisa , Revisões Sistemáticas como Assunto/métodos , Humanos , Prognóstico
15.
Oncoimmunology ; 10(1): 1939601, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34249474

RESUMO

Although pharmacological stimulation of TLRs has anti-tumor effects, it has not been determined whether endogenous stimulation of TLRs can lead to tumor rejection. Herein, we demonstrate the existence of an innate anti-glioma NK-mediated circuit initiated by glioma-released miR-1983 within exosomes, and which is under the regulation of galectin-1 (Gal-1). We demonstrate that miR-1983 is an endogenous TLR7 ligand that activates TLR7 in pDCs and cDCs through a 5'-UGUUU-3' motif at its 3' end. TLR7 activation and downstream signaling through MyD88-IRF5/IRF7 stimulates secretion of IFN-ß. IFN-ß then stimulates NK cells resulting in the eradication of gliomas. We propose that successful immunotherapy for glioma could exploit this endogenous innate immune circuit to activate TLR7 signaling and stimulate powerful anti-glioma NK activity, at least 10-14 days before the activation of anti-tumor adaptive immunity.


Assuntos
Galectina 1 , Glioma , Receptor 7 Toll-Like , Galectina 1/genética , Glioma/genética , Humanos , Fatores Reguladores de Interferon , Interferon beta , Células Matadoras Naturais/metabolismo , Licenciamento , MicroRNAs , Receptor 7 Toll-Like/genética
16.
Nat Genet ; 53(8): 1221-1232, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34294917

RESUMO

Driver mutations in genes encoding histone H3 proteins resulting in p.Lys27Met substitutions (H3-K27M) are frequent in pediatric midline brain tumors. However, the precise mechanisms by which H3-K27M causes tumor initiation remain unclear. Here, we use human hindbrain neural stem cells to model the consequences of H3.3-K27M on the epigenomic landscape in a relevant developmental context. Genome-wide mapping of epitope-tagged histone H3.3 revealed that both the wild type and the K27M mutant incorporate abundantly at pre-existing active enhancers and promoters, and to a lesser extent at Polycomb repressive complex 2 (PRC2)-bound regions. At active enhancers, H3.3-K27M leads to focal H3K27ac loss, decreased chromatin accessibility and reduced transcriptional expression of nearby neurodevelopmental genes. In addition, H3.3-K27M deposition at a subset of PRC2 target genes leads to increased PRC2 and PRC1 binding and augmented transcriptional repression that can be partially reversed by PRC2 inhibitors. Our work suggests that, rather than imposing de novo transcriptional circuits, H3.3-K27M drives tumorigenesis by locking initiating cells in their pre-existing, immature epigenomic state, via disruption of PRC2 and enhancer functions.


Assuntos
Elementos Facilitadores Genéticos , Histonas/metabolismo , Células-Tronco Neurais/fisiologia , Complexo Repressor Polycomb 2/genética , Rombencéfalo/citologia , Animais , Neoplasias Encefálicas/genética , Diferenciação Celular/genética , Linhagem Celular , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Epigenoma , Regulação da Expressão Gênica no Desenvolvimento , Glioma/genética , Histonas/genética , Humanos , Lisina/metabolismo , Masculino , Camundongos Endogâmicos , Mutação , Células-Tronco Neurais/transplante , Oncogenes , Complexo Repressor Polycomb 2/antagonistas & inibidores , Complexo Repressor Polycomb 2/metabolismo , Regiões Promotoras Genéticas , Rombencéfalo/fisiologia
17.
Front Immunol ; 12: 557994, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220791

RESUMO

The immunosuppressive mechanisms of the surrounding microenvironment and distinct immunogenomic features in glioblastoma (GBM) have not been elucidated to date. To fill this gap, useful data were extracted from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), GSE16011, GSE43378, GSE23806, and GSE12907. With the ssGSEA method and the ESTIMATE and CIBERSORT algorithms, four microenvironmental signatures were used to identify glioma microenvironment genes, and the samples were reasonably classified into three immune phenotypes. The molecular and clinical features of these phenotypes were characterized via key gene set expression, tumor mutation burden, fraction of immune cell infiltration, and functional enrichment. Exhausted CD8+ T cell (GET) signature construction with the predictive response to commonly used antitumor drugs and peritumoral edema assisted in further characterizing the immune phenotype features. A total of 2,466 glioma samples with gene expression profiles were enrolled. Tumor purity, ESTIMATE, and immune and stromal scores served as the 4 microenvironment signatures used to classify gliomas into immune-high, immune-middle and immune-low groups, which had distinct immune heterogeneity and clinicopathological characteristics. The immune-H phenotype had higher expression of four immune signatures; however, most checkpoint molecules exhibited poor survival. Enriched pathways among the subtypes were related to immunity. The GET score was similar among the three phenotypes, while immune-L was more sensitive to bortezomib, cisplatin, docetaxel, lapatinib, and rapamycin prescriptions and displayed mild peritumor edema. The three novel immune phenotypes with distinct immunogenetic features could have utility for understanding glioma microenvironment regulation and determining prognosis. These results contribute to classifying glioma subtypes, remodeling the immunosuppressive microenvironment and informing novel cancer immunotherapy in the era of precision immuno-oncology.


Assuntos
Neoplasias Encefálicas/genética , Linfócitos T CD8-Positivos/imunologia , Glioblastoma/genética , Glioma/genética , Linfócitos do Interstício Tumoral/imunologia , Algoritmos , Antineoplásicos , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidade , Edema , Regulação Neoplásica da Expressão Gênica , Genoma , Glioblastoma/diagnóstico , Glioblastoma/mortalidade , Glioma/diagnóstico , Glioma/mortalidade , Humanos , Imunogenética/métodos , Imunofenotipagem , Prognóstico , Análise de Sobrevida , Transcriptoma , Microambiente Tumoral/genética
18.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299002

RESUMO

Culinary sage (Salvia officinalis L.) is a common spice plant in the mint family (Lamiaceae) well known for its distinctive culinary and traditional medicinal uses. Sage tea has been used traditionally as a brain-enhancing tonic and extracts from sage have been reported to have both cognitive and memory enhancing effects. Brain-derived neurotrophic factor (BDNF) is an endogenous signaling molecule involved in cognition and memory function. In this study, activity-guided fractionation employing preparative reverse-phase high performance liquid chromatography (RP-HPLC) of culinary sage extracts led to the discovery of benzyl 6-O-ß-D-apiofuranosyl-ß-D-glucoside (B6AG) as a natural product that upregulates transcription of neurotrophic factors in C6 glioma cells. Purified B6AG showed a moderate dose response, with upregulation of BDNF and with EC50 at 6.46 µM. To better understand the natural variation in culinary sage, B6AG was quantitated in the leaves of several commercial varieties by liquid chromatography-mass spectrometry (LC-MS). The level of B6AG in dried culinary sage was found to range from 334 ± 14 to 698 ± 65 µg/g. This study provided a foundation for future investigations, including quantitative inquiries on the distribution of B6AG within the different plant organs, explorations in optimizing post-harvest practices, and aid in the development of sage varieties with elevated levels of B6AG.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Glioma/metabolismo , Folhas de Planta/química , Salvia officinalis/química , Transdução de Sinais/efeitos dos fármacos , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Glioma/genética , Espectrometria de Massas , Ratos , Transdução de Sinais/genética
19.
Stem Cell Res Ther ; 12(1): 394, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34256854

RESUMO

BACKGROUND: The tumour microenvironment contributes to chemotherapy resistance in gliomas, and glioma-associated mesenchymal stromal/stem cells (gaMSCs) are important stromal cell components that play multiple roles in tumour progression. However, whether gaMSCs affect chemotherapy resistance to the first-line agent temozolomide (TMZ) remains unclear. Herein, we explored the effect and mechanism of gaMSCs on resistance to TMZ in glioma cells. METHODS: Human glioma cells (cell line U87MG and primary glioblastoma cell line GBM-1) were cultured in conditioned media of gaMSCs and further treated with TMZ. The proliferation, apoptosis and migration of glioma cells were detected by Cell Counting Kit-8 (CCK-8), flow cytometry and wound-healing assays. The expression of FOXS1 in glioma cells was analysed by gene microarray, PCR and Western blotting. Then, FOXS1 expression in glioma cells was up- and downregulated by lentivirus transfection, and markers of the epithelial-mesenchymal transformation (EMT) process were detected. Tumour-bearing nude mice were established with different glioma cells and treated with TMZ to measure tumour size, survival time and Ki-67 expression. Finally, the expression of IL-6 in gaMSC subpopulations and its effects on FOXS1 expression in glioma cells were also investigated. RESULTS: Conditioned media of gaMSCs promoted the proliferation, migration and chemotherapy resistance of glioma cells. The increased expression of FOXS1 and activation of the EMT process in glioma cells under gaMSC-conditioned media were detected. The relationship of FOXS1, EMT and chemotherapy resistance in glioma cells was demonstrated through the regulation of FOXS1 expression in vitro and in vivo. Moreover, FOXS1 expression in glioma cells was increased by secretion of IL-6 mainly from the CD90low gaMSC subpopulation. CONCLUSIONS: CD90low gaMSCs could increase FOXS1 expression in glioma cells by IL-6 secretion, thereby activating epithelial-mesenchymal transition and resistance to TMZ in glioma cells. These results indicate a new role of gaMSCs in chemotherapy resistance and provide novel therapeutic targets.


Assuntos
Neoplasias Encefálicas , Glioma , Animais , Apoptose , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal , Glioma/tratamento farmacológico , Glioma/genética , Camundongos , Camundongos Nus , Células-Tronco , Temozolomida/farmacologia , Microambiente Tumoral
20.
J Proteome Res ; 20(8): 3977-3991, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34286978

RESUMO

Human malignant gliomas are the most common type of primary brain tumor. Composed of glial cells and their precursors, they are aggressive and highly invasive, leading to a poor prognosis. Due to the difficulty of surgically removing tumors and their resistance to treatments, novel therapeutic approaches are needed to improve patient life expectancy and comfort. Drosophila melanogaster is a compelling genetic model to better understanding human neurological diseases owing to its high conservation in signaling pathways and cellular content of the brain. Here, glioma has been induced in Drosophila by co-activating the epidermal growth factor receptor and the phosphatidyl-inositol-3 kinase signaling pathways. Complementary nuclear magnetic resonance (NMR) techniques were used to obtain metabolic profiles in the third instar larvae brains. Fresh organs were directly studied by 1H high resolution-magic angle spinning (HR-MAS) NMR, and brain extracts were analyzed by solution-state 1H-NMR. Statistical analyses revealed differential metabolic signatures, impacted metabolic pathways, and glioma biomarkers. Each method was efficient to determine biomarkers. The highlighted metabolites including glucose, myo-inositol, sarcosine, glycine, alanine, and pyruvate for solution-state NMR and proline, myo-inositol, acetate, and glucose for HR-MAS show very good performances in discriminating samples according to their nature with data mining based on receiver operating characteristic curves. Combining results allows for a more complete view of induced disturbances and opens the possibility of deciphering the biochemical mechanisms of these tumors. The identified biomarkers provide a means to rebalance specific pathways through targeted metabolic therapy and to study the effects of pharmacological treatments using Drosophila as a model organism.


Assuntos
Drosophila melanogaster , Glioma , Animais , Biomarcadores , Glioma/diagnóstico por imagem , Glioma/genética , Humanos , Espectroscopia de Ressonância Magnética , Metabolômica
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