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1.
Medicine (Baltimore) ; 99(33): e21196, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32871983

RESUMO

INTRODUCTION: Circulating tumor DNA (ctDNA) has provided a minimally invasive approach for the detection of genetic mutations in glioma. However, the diagnostic value of ctDNA in glioma remains unclear. This meta-analysis was designed to investigate the diagnostic value of ctDNA, compared with the current "criterion standard" tumor tissues. MATERIALS AND METHODS: The included studies were collected by searching PubMed, Web of Science, Cochrane Library, and Embase databases. All statistical analyses were performed using the STATA12.0 and Meta-DiSc1.4 software. RESULT: A total of 11 studies comprising 522 glioma patients met our inclusion criteria. The pooled sensitivity and specificity were 0.69 (95% confidence interval [CI] 0.66-0.73) and 0.98 (95% CI 0.96-0.99), respectively. The pooled diagnostic odds ratio was 23.27 (95% CI 13.69-39.53) and the area under the curve of the summary receiver operating characteristics curve was 0.90 (95% CI 0.89-0.92). CONCLUSIONS: ctDNA analysis is an effective method to detect the genetic mutation status in glioma patients with high specificity and relatively moderate sensitivity. The application of high-throughput technologies, the detection of patients with high-grade glioma, and sampling from cerebrospinal fluid could have higher diagnostic accuracy. The improvement of detection methods and more large-sample case-control studies are required in the future.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/genética , DNA Tumoral Circulante , Glioma/diagnóstico , Glioma/genética , Biomarcadores Tumorais/análise , DNA Tumoral Circulante/análise , Humanos
2.
Anticancer Res ; 40(9): 5141-5149, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878802

RESUMO

BACKGROUND/AIM: This study investigated the effects of temozolomide (TMZ) and/or checkpoint kinase inhibitor AZD7762 in human glioma cells. MATERIALS AND METHODS: Glioma cells were treated with TMZ and/or AZD7762 for 24 or 48 h, then the cellular survival was studied and the expression of various proteins was investigated. RESULTS: Both TMZ and AZD7762 induced concentration- and time-dependent cytotoxic effects, and combined TMZ and AZD7762 (TMZ+AZD) caused synergistic cytotoxic effects in glioma cells (p<0.05). AZD7762 suppressed the O6-methylguanine-DNA-methyltransferase (MGMT) expression. TMZ+AZD increased the expression of phospho-p53 (p-p53), p-p38 mitogen-activated protein kinase, and phosphatase and tensin homolog; and decreased the expression of p-extracellular signal-regulated kinase 1/2 and p-signal transducer and activator of transcription 3 in glioma cells. CONCLUSION: TMZ and AZD7762 combined induced synergistic cytotoxic effects on human glioma cells and such effects may be related to the AZD7762-induced suppression of MGMT expression and the modulation of multiple signaling pathways.


Assuntos
Antineoplásicos/farmacologia , Temozolomida/farmacologia , Tiofenos/farmacologia , Ureia/análogos & derivados , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/genética , Glioma/metabolismo , Humanos , Ureia/farmacologia
3.
Nat Commun ; 11(1): 3883, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32753598

RESUMO

Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that the MGMT genomic rearrangements contribute to TMZ resistance both in vitro and in vivo. Lastly, we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Rearranjo Gênico , Glioma/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Temozolomida/farmacologia , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Animais , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Adutos de DNA/efeitos dos fármacos , Adutos de DNA/metabolismo , Metilação de DNA , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Regiões Promotoras Genéticas/genética , RNA-Seq , Temozolomida/uso terapêutico , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima , Sequenciamento Completo do Genoma , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
4.
Brain Tumor Pathol ; 37(4): 136-144, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32761533

RESUMO

Oncogenic gene fusions have been reported in diffuse gliomas and may serve as potential therapeutic targets. Here, using next-generation sequencing analysis (Illumina TruSight Tumor 170 panel), we analyzed a total of 356 diffuse gliomas collected from 2017 to 2019 to evaluate clinical, pathological, and genetic features of gene fusion. We found 53 cases of glioblastomas harboring the following oncogenic gene fusions: MET (n = 18), EGFR (n = 14), FGFR (n = 12), NTRK (n = 5), RET (n = 2), AKT3 (n = 1), and PDGFRA fusions (n = 1). Gene fusions were consistently observed in both IDH-wildtype and IDH-mutant glioblastomas (8.8% and 9.4%, p = 1.000). PTPRZ1-MET fusion was the only fusion that genetically resembled secondary glioblastomas (i.e., high frequency of IDH mutation, ATRX loss, TP53 mutation, and absence of EGFR amplification), whereas other gene fusion types were similar to primary glioblastomas (i.e., high frequency of IDH-wildtype, TERT mutation, EGFR amplification, and PTEN mutation). In IDH-wildtype glioblastoma patients, multivariable analysis revealed that the PTPRZ1-MET fusion was associated with poor progression-free survival (HR [95% CI]: 5.42 (1.72-17.05), p = 0.004). Additionally, we described two novel cases of CCDC6-RET fusion in glioma. Collectively, our findings indicate that targetable gene fusions are associated with aggressive biological behavior and can aid the clinical treatment strategy for glioma patients.


Assuntos
Neoplasias Encefálicas/genética , Fusão Gênica/genética , Estudos de Associação Genética , Glioblastoma/genética , Glioma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Proteínas do Citoesqueleto/genética , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Glioma/mortalidade , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-ret/genética , Taxa de Sobrevida
5.
Mol Cell ; 79(3): 376-389.e8, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32640193

RESUMO

Activation of dual-specificity tyrosine-phosphorylation-regulated kinases 1A and 1B (DYRK1A and DYRK1B) requires prolyl hydroxylation by PHD1 prolyl hydroxylase. Prolyl hydroxylation of DYRK1 initiates a cascade of events leading to the release of molecular constraints on von Hippel-Lindau (VHL) ubiquitin ligase tumor suppressor function. However, the proline residue of DYRK1 targeted by hydroxylation and the role of prolyl hydroxylation in tyrosine autophosphorylation of DYRK1 are unknown. We found that a highly conserved proline in the CMGC insert of the DYRK1 kinase domain is hydroxylated by PHD1, and this event precedes tyrosine autophosphorylation. Mutation of the hydroxylation acceptor proline precludes tyrosine autophosphorylation and folding of DYRK1, resulting in a kinase unable to preserve VHL function and lacking glioma suppression activity. The consensus proline sequence is shared by most CMGC kinases, and prolyl hydroxylation is essential for catalytic activation. Thus, formation of prolyl-hydroxylated intermediates is a novel mechanism of kinase maturation and likely a general mechanism of regulation of CMGC kinases in eukaryotes.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Isoenzimas/genética , Prolina/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Sequência de Aminoácidos , Animais , Sítios de Ligação , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Glioma/patologia , Células HEK293 , Xenoenxertos , Humanos , Hidroxilação , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Isoenzimas/química , Isoenzimas/metabolismo , Camundongos , Camundongos Nus , Proteína Quinase 14 Ativada por Mitógeno/química , Proteína Quinase 14 Ativada por Mitógeno/genética , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Mutação , Neuroglia/metabolismo , Neuroglia/patologia , Fosforilação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
7.
PLoS One ; 15(7): e0236045, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32692766

RESUMO

Epigenetic age acceleration-the difference between an individual's DNA methylation age and chronological age-is associated with many diseases including cancer. This study aims to evaluate epigenetic age acceleration as a prognostic biomarker for gliomas. DNA methylation data of gliomas patients (516 low-grade and intermediate-grade gliomas and 140 glioblastoma) were obtained from The Cancer Genome Atlas (TCGA) and patient epigenetic ages were computed using Horvath's age prediction model. We used multivariate linear regression to assess the association of epigenetic age acceleration with tumor molecular subtypes, including Codel, Classic-like, G-CIMP-high, G-CIMP-low, Mesenchymal-like and PA-like. Compared with Codel subtype, epigenetic ages in other molecular subtypes show deceleration after controlling age and race. Age deceleration for Classic-like, G-CIMP-high, G-CIMP-low, Mesenchymal-like and PA-like were 15.42 years (CI: 7.98-22.86, p = 5.38E-05), 25.00 years (CI: 20.79-29.22, p = 4.06E-28), 28.56 years (CI: 14.37-42.74, p = 8.75E-05), 45.34 years (CI: 38.80-51.88, p = 2.15E-36), and 53.58 years (CI: 44.90-62.26, p = 4.81E-30), respectively. Then, Cox proportional hazards regression was used to assess the association of epigenetic age acceleration with patient overall survival. Our results show epigenetic age acceleration is positively associated with patient overall survival (per 10-year age acceleration, HR = 0.89; 95%CI: 0.82-0.97; p = 9.04E-03) in multivariate analysis. When stratified by molecular subtypes, epigenetic age acceleration remains positively associated with patient survival after adjusting age and tumor grade. In conclusion, epigenetic age acceleration is significantly associated with molecular subtypes and patient overall survival in gliomas, indication that epigenetic age acceleration has potential as a quantitative prognostic biomarker for gliomas.


Assuntos
Envelhecimento/genética , Epigênese Genética , Glioma/diagnóstico , Glioma/genética , Adulto , Metilação de DNA , Feminino , Glioma/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida
9.
BMC Neurol ; 20(1): 259, 2020 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-32600353

RESUMO

BACKGROUND: To investigate associations between lower-grade glioma (LGG) mRNA-based subtypes (R1-R4) and MR features. METHODS: mRNA-based subtyping was obtained from the LGG dataset in The Cancer Genome Atlas (TCGA). We identified matching patients (n = 145) in The Cancer Imaging Archive (TCIA) who underwent MR imaging. The associations between mRNA-based subtypes and MR features were assessed. RESULTS: In the TCGA-LGG dataset, patients with the R2 subtype had the shortest median OS months (P < 0.05). The time-dependent ROC for the R2 subtype was 0.78 for survival at 12 months, 0.76 for survival at 24 months, and 0.76 for survival at 36 months. In the TCIA-LGG dataset, 41 (23.7%) R1 subtype, 40 (23.1%) R2 subtype, 19 (11.0%) R3 subtype and 45 (26.0%) R4 subtype cases were identified. Multivariate analysis revealed that enhancing margin (ill-defined, OR: 9.985; P = 0.003) and T1 + C/T2 mismatch (yes, OR: 0.091; P = 0.023) were associated with the R1 subtype (AUC: 0.708). The average accuracy of the ten-fold cross validation was 71%. Proportion of contrast-enhanced (CE) tumour (> 5%, OR: 14.733; P < 0.001) and necrosis/cystic changes (yes, OR: 0.252; P = 0.009) were associated with the R2 subtype (AUC: 0.832). The average accuracy of the ten-fold cross validation was 82%. Haemorrhage (yes, OR: 8.55; P < 0.001) was positively associated with the R3 subtype (AUC: 0.689). The average accuracy of the ten-fold cross validation was 87%. Proportion of CE tumour (> 5%, OR: 0.14; P < 0.001) was negatively associated with the R4 subtype (AUC: 0.672). The average accuracy of the ten-fold cross validation was 71%. For the prediction of the R2 subtype, the nomogram showed good discrimination and calibration. Decision curve analysis demonstrated that prediction with the R2 model was clinically useful. CONCLUSIONS: Patients with the R2 subtype had the worst prognosis. We demonstrated that MRI features can identify distinct LGG mRNA-based molecular subtypes.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Glioma/diagnóstico por imagem , Glioma/genética , RNA Mensageiro/genética , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Feminino , Genômica/métodos , Glioma/mortalidade , Glioma/patologia , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
Zhonghua Yi Xue Za Zhi ; 100(21): 1634-1639, 2020 Jun 02.
Artigo em Chinês | MEDLINE | ID: mdl-32486598

RESUMO

Objective: To screen the different microRNAs in the serum exosomes of patients with malignant glioma, to explore the effect of non-coding microRNA-376b-3p (miR-376b-3p) on the proliferation, invasion and tumor vasculogenic mimicry of glioma cells, and to verify its targeting effect on HOXD10. Methods: HiSeq/MiSeq high-throughput sequencing was used to screen the different microRNA expression profiles, target genes and action pathways in the serum exosomes of patients with malignant glioma. Samples were used to evaluate the expression of candidate microRNAs in serum exosomes of high-grade gliomas. The effects of miR-376b-3p on the proliferation, invasion and angiogenesis of glioma cells were detected by MTT assay, Transwell migration assay and Matrigel vasculogenic mimicry assay. The mRNA and protein expression of HOXD10 were detected to evaluate the regulatory effect of miR-376b-3p on it. Results: There were 144 different expression microRNAs in the serum exosomes between malignant glioma and the normal control. Focal adhesion and tumor protein polysaccharides were involved in the regulation of glioma enriched by KEGG(Kyoto Encyclopedia of Genes and Genomes). MiR-376b-3p was down regulated in malignant glioma, and AUC of malignant glioma was 0.85 (P<0.01). MTT test showed that the proliferation ability of miR-376b-3p inhibitor group was higher than that of the control group, and that of miR-376b-3p mimic group was lower than that of the control group. Transwell migration test showed that the number of transmembrane cells in miR-376b-3p inhibitor group was higher than that in NC inhibitor group, and the number of transmembrane cells in miR-376b-3p mimic group was lower than that in NC mimic group. The number of tubes of vasculogenic mimicry in miR-376b-3p mimic group was lower than that in NC mimic group. MiR-376b-3p inhibitor decreased the expression level of HOXD10 mRNA and protein, and miR-376b-3p mimic increased the expression level of HOXD10 mRNA and protein. Conclusions: MiR-376b-3p is down-regulated in the serum exosomes of malignant glioma patients. The up-regulated miR-376b-3p can reduce the proliferation and invasion of glioma cells, inhibit the formation of vasculogenic mimicry, and increase the expression of HOXD10, which is expected to inhibit the formation of two forms of angiogenesis at the same time. MiR-376b-3p may be a new therapeutic target of anti-angiogenesis for malignant glioma.


Assuntos
Exossomos , Glioma , MicroRNAs/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Humanos , RNA Mensageiro
12.
Brain Tumor Pathol ; 37(3): 81-88, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32529280

RESUMO

The objective of this study is to clarify clinical significance of the H3F3A K27M mutation (H3K27M) and analyze the correlation between H3K27M, H3K27me3 status, and EZH2 expression and prognosis in spinal cord gliomas. Patients with spinal cord diffuse glioma regardless of World Health Organization (WHO) grade underwent genetic analysis for H3F3A, HIST1H3B, TERT promoter, IDH1/2, and BRAF. H3K27me3 status and EZH2 expression were analyzed through immunohistochemistry. Thereafter, the association between H3K27M, H3K27me3 status, and EZH2 expression and prognosis was retrospectively analyzed using the log-rank test. A total of 26 cases, 5 with WHO grade 4, 9 with grade 3, and 12 with grade 2 glioma, were analyzed. Although WHO grade 2 cases tended to present favorable overall survival, the difference was not statistically significant. H3K27M, which was detected in four grade 4 cases (80%) and three grade 3 cases (33%), was not associated with prognosis among grade 3 and 4 cases. Among WHO grade 2-4 cases, the combination of retained H3K27me3 and negative EZH2 expression was correlated with favorable overall survival (p = 0.03). The combination of H3K27me3 status and EZH2 expression was considered as a potential prognostic marker in WHO grade 2-4 diffuse spinal cord gliomas.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Expressão Gênica , Glioma/genética , Histonas/metabolismo , Mutação de Sentido Incorreto , Neoplasias da Medula Espinal/genética , Glioma/terapia , Histonas/genética , Humanos , Metilação , Prognóstico , Estudos Retrospectivos , Neoplasias da Medula Espinal/terapia
13.
Nat Commun ; 11(1): 3169, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576825

RESUMO

Understanding tumor metabolism holds the promise of new insights into cancer biology, diagnosis and treatment. To assess human cancer metabolism, here we report a method to collect intra-operative samples of blood from an artery directly upstream and a vein directly downstream of a brain tumor, as well as samples from dorsal pedal veins of the same patients. After performing targeted metabolomic analysis, we characterize the metabolites consumed and produced by gliomas in vivo by comparing the arterial supply and venous drainage. N-acetylornithine, D-glucose, putrescine, and L-acetylcarnitine are consumed in relatively large amounts by gliomas. Conversely, L-glutamine, agmatine, and uridine 5-monophosphate are produced in relatively large amounts by gliomas. Further we verify that D-2-hydroxyglutarate (D-2HG) is high in venous plasma from patients with isocitrate dehydrogenases1 (IDH1) mutations. Through these paired comparisons, we can exclude the interpatient variation that is present in plasma samples usually taken from the cubital vein.


Assuntos
Biomarcadores Tumorais/sangue , Vasos Sanguíneos/metabolismo , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/metabolismo , Glioma/sangue , Glioma/metabolismo , Metabolômica , Acetilcarnitina/sangue , Adulto , Idoso , Agmatina/sangue , Sangue , Análise Química do Sangue , Glicemia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Feminino , Glioma/diagnóstico por imagem , Glioma/genética , Glucose , Glutamina/sangue , Glutaratos/sangue , Humanos , Isocitrato Desidrogenase/sangue , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-Idade , Ornitina/análogos & derivados , Ornitina/sangue , Putrescina/sangue , Uridina Monofosfato/sangue , Adulto Jovem
14.
Mol Cell ; 79(1): 167-179.e11, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32497496

RESUMO

The identification of microRNA (miRNA) targets by Ago2 crosslinking-immunoprecipitation (CLIP) methods has provided major insights into the biology of this important class of non-coding RNAs. However, these methods are technically challenging and not easily applicable to an in vivo setting. To overcome these limitations and facilitate the investigation of miRNA functions in vivo, we have developed a method based on a genetically engineered mouse harboring a conditional Halo-Ago2 allele expressed from the endogenous Ago2 locus. By using a resin conjugated to the HaloTag ligand, Ago2-miRNA-mRNA complexes can be purified from cells and tissues expressing the endogenous Halo-Ago2 allele. We demonstrate the reproducibility and sensitivity of this method in mouse embryonic stem cells, developing embryos, adult tissues, and autochthonous mouse models of human brain and lung cancers. This method and the datasets we have generated will facilitate the characterization of miRNA-mRNA networks in vivo under physiological and pathological conditions.


Assuntos
Proteínas Argonauta/fisiologia , Células-Tronco Embrionárias/metabolismo , Glioma/metabolismo , MicroRNAs/metabolismo , RNA Mensageiro/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Animais , Células-Tronco Embrionárias/citologia , Feminino , Regulação da Expressão Gênica , Glioma/genética , Glioma/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Hidrolases/genética , Camundongos , Camundongos Knockout , MicroRNAs/genética , Ligação Proteica , RNA Mensageiro/genética , Proteínas Recombinantes de Fusão/genética
15.
Nat Commun ; 11(1): 2977, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532995

RESUMO

Independent scientific achievements have led to the discovery of aberrant splicing patterns in oncogenesis, while more recent advances have uncovered novel gene fusions involving neurotrophic tyrosine receptor kinases (NTRKs) in gliomas. The exploration of NTRK splice variants in normal and neoplastic brain provides an intersection of these two rapidly evolving fields. Tropomyosin receptor kinase B (TrkB), encoded NTRK2, is known for critical roles in neuronal survival, differentiation, molecular properties associated with memory, and exhibits intricate splicing patterns and post-translational modifications. Here, we show a role for a truncated NTRK2 splice variant, TrkB.T1, in human glioma. TrkB.T1 enhances PDGF-driven gliomas in vivo, augments PDGF-induced Akt and STAT3 signaling in vitro, while next generation sequencing broadly implicates TrkB.T1 in the PI3K signaling cascades in a ligand-independent fashion. These TrkB.T1 findings highlight the importance of expanding upon whole gene and gene fusion analyses to include splice variants in basic and translational neuro-oncology research.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Glicoproteínas de Membrana/genética , Oncogenes/genética , Isoformas de RNA/genética , Processamento de RNA , Receptor trkB/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Células Cultivadas , Perfilação da Expressão Gênica , Ontologia Genética , Glioma/metabolismo , Glioma/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Glicoproteínas de Membrana/metabolismo , Camundongos , Células NIH 3T3 , Células-Tronco Neurais/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Isoformas de RNA/metabolismo , Receptor trkB/metabolismo , Transdução de Sinais/genética
16.
Life Sci ; 256: 117897, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32502543

RESUMO

Glioma is the most common brain malignancy and surgical resection is the primary option for patient with glioma. Anesthetics could be used to inhibit cancer dissemination and metastasis during surgery. This study aims to assess the function of volatile anesthetic sevoflurane in glioma migration and invasion and explore the potential mechanism. Twenty-five patients with glioma were recruited in this study. LN229 and U251 cells were used in vitro experiments. Cell viability was analyzed by MTT analysis. Cell migration and invasion were examined via transwell analysis. microRNA-34a-5p (miR-34a-5p) and matrix metalloproteinase-2 (MMP-2) levels were measured via quantitative real-time polymerase chain reaction. The relationship of miR-34a-5p and MMP-2 was tested via bioinformatics analysis, luciferase reporter analysis, RNA immunoprecipitation and RNA pull-down. Sevoflurane decreased glioma cell migration and invasion. In glioma cells, sevoflurane up-regulated miR-34a-5p abundance and down-regulated MMP-2 level. Overexpression of miR-34a-5p contributed to sevoflurane-caused suppression of migration and invasion, while its knockdown played an opposite effect. MMP-2 was targeted via miR-34a-5p and MMP-2 silence reversed the influence of miR-34a-5p knockdown under sevoflurane. Sevoflurane exposure represses cell migration and invasion, which might be related to inhibition of MMP-2 by up-regulating miR-34a-5p. This study provides a novel mechanism for understanding the pharmacological effects of sevoflurane on glioma.


Assuntos
Neoplasias Encefálicas/patologia , Movimento Celular/efeitos dos fármacos , Glioma/patologia , Metaloproteinase 2 da Matriz/metabolismo , MicroRNAs/metabolismo , Sevoflurano/farmacologia , Sequência de Bases , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Glioma/enzimologia , Glioma/genética , Humanos , MicroRNAs/genética , Invasividade Neoplásica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para Cima/efeitos dos fármacos
17.
Nat Commun ; 11(1): 3015, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32541784

RESUMO

The interplay between glioma stem cells (GSCs) and the tumor microenvironment plays crucial roles in promoting malignant growth of glioblastoma (GBM), the most lethal brain tumor. However, the molecular mechanisms underlying this crosstalk are incompletely understood. Here, we show that GSCs secrete the Wnt-induced signaling protein 1 (WISP1) to facilitate a pro-tumor microenvironment by promoting the survival of both GSCs and tumor-associated macrophages (TAMs). WISP1 is preferentially expressed and secreted by GSCs. Silencing WISP1 markedly disrupts GSC maintenance, reduces tumor-supportive TAMs (M2), and potently inhibits GBM growth. WISP1 signals through Integrin α6ß1-Akt to maintain GSCs by an autocrine mechanism and M2 TAMs through a paracrine manner. Importantly, inhibition of Wnt/ß-catenin-WISP1 signaling by carnosic acid (CA) suppresses GBM tumor growth. Collectively, these data demonstrate that WISP1 plays critical roles in maintaining GSCs and tumor-supportive TAMs in GBM, indicating that targeting Wnt/ß-catenin-WISP1 signaling may effectively improve GBM treatment and the patient survival.


Assuntos
Neoplasias Encefálicas/genética , Proteínas de Sinalização Intercelular CCN/genética , Glioma/genética , Macrófagos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Proteínas de Sinalização Intercelular CCN/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Doxiciclina/farmacologia , Glioma/metabolismo , Glioma/terapia , Humanos , Estimativa de Kaplan-Meier , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Transdução de Sinais/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Células U937 , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
18.
Nat Commun ; 11(1): 3077, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32555164

RESUMO

Brainstem gliomas are a heterogeneous group of tumors that encompass both benign tumors cured with surgical resection and highly lethal cancers with no efficacious therapies. We perform a comprehensive study incorporating epigenetic and genomic analyses on a large cohort of brainstem gliomas, including Diffuse Intrinsic Pontine Gliomas. Here we report, from DNA methylation data, distinct clusters termed H3-Pons, H3-Medulla, IDH, and PA-like, each associated with unique genomic and clinical profiles. The majority of tumors within H3-Pons and-H3-Medulla harbors H3F3A mutations but shows distinct methylation patterns that correlate with anatomical localization within the pons or medulla, respectively. Clinical data show significantly different overall survival between these clusters, and pathway analysis demonstrates different oncogenic mechanisms in these samples. Our findings indicate that the integration of genetic and epigenetic data can facilitate better understanding of brainstem gliomagenesis and classification, and guide future studies for the development of novel treatments for this disease.


Assuntos
Neoplasias do Tronco Encefálico/genética , Epigenoma , Glioma/genética , Adolescente , Adulto , Neoplasias do Tronco Encefálico/mortalidade , Criança , Pré-Escolar , Análise por Conglomerados , Metilação de DNA , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genômica , Glioma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Life Sci ; 255: 117792, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32416168

RESUMO

AIMS: Sex-determining region of Y chromosome-related high-mobility-group box 15 (SOX15) has recently emerged as a candidate tumor-inhibitor in multiple types of human tumors. To date, the involvement of SOX15 in glioma is undetermined. The purpose of this study was to investigate the expression, function and potential molecular mechanism of SOX15 in glioma. MAIN METHODS: Relative mRNA expression was analyzed by real-time quantitative PCR. Protein expression was determined by Western blot. Cell proliferation was assessed by cell counting kit-8 and colony formation assay. Cell invasion was evaluated by Matrigel invasion assay. Wnt/ß-catenin activation was monitored by luciferase reporter assay. KEY FINDINGS: SOX15 expression was decreased in glioma tissues and cell lines compared with normal controls. Kaplan-Meier analysis revealed that patients with low expression of SOX15 had shorter survival than those who had high expression of SOX15. The upregulation of SOX15 markedly repressed the proliferation and invasion of glioma cells, whereas its depletion enhanced glioma cell proliferation and invasion. Research into the mechanism revealed that SOX15 exerted an inhibitory effect on Wnt/ß-catenin signaling in glioma cells. Notably, overexpression of ß-catenin partially reversed the SOX15 overexpression-mediated tumor-suppressive effect. In addition, SOX15 overexpression significantly impeded tumor formation by glioma cells in vivo in a mouse xenograft model associated with downregulation of active ß-catenin expression. SIGNIFICANCE: These data demonstrate that SOX15 functions as a potential tumor-suppressor in glioma by inhibiting cell proliferation and invasion via the downregulation of Wnt/ß-catenin signaling.


Assuntos
Neoplasias Encefálicas/patologia , Glioma/patologia , Fatores de Transcrição SOX/genética , Via de Sinalização Wnt/genética , Animais , Neoplasias Encefálicas/genética , Proliferação de Células/genética , Regulação para Baixo , Glioma/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/genética , Taxa de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismo
20.
Anticancer Res ; 40(5): 2777-2785, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366424

RESUMO

BACKGROUND/AIM: Understanding of the molecular events associated with progression and survival differences in patients with lower-grade gliomas (LGGs) is still unclear. The comparison of findings across studies using different datasets and methods is essential for a new molecular-based classification system. The aim of the study was to identify biomarkers for prognostic classification of patients with LGGs, and furthermore to lay a foundation for future development of targeted therapies for LGGs. PATIENTS AND METHODS: Using information-theoretic and statistical approaches, we analyzed mRNA expression data for 18,413 genes from LGG samples in order to identify candidate biomarkers for survival. The candidate genes were then evaluated for their potential as prognostic biomarkers using multivariable Cox regression analyses that adjusted for the effects of age and grade. RESULTS: WEE1, EMP3, E2F7, CD58 and NSUN7 genes were identified as candidate biomarkers of LGGs and their high expression was associated with significantly shorter survival. The hazard ratios for mortality were 5.02 (95% CI=3.40-7.40) for WEE1, 5.45 (95% CI=3.63-8.18) for EMP3, 4.49 (95% CI=3.03-6.66) for E2F7, 4.77 (95% CI=3.22-7.06) for CD58 and 4.38 (95% CI=2.97-6.47) for NSUN7. In addition, the expression pattern of these genes, associated with shorter survival in LGGs, was also observed in glioblastoma multiforme. CONCLUSION: Identification of genes associated with poor outcomes will provide insights into novel biological mechanisms that may lead to improvement in progression and survival for patients with LGGs.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Neoplasias Encefálicas/mortalidade , Progressão da Doença , Feminino , Glioma/mortalidade , Humanos , Masculino , Gradação de Tumores , Análise de Sobrevida
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