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1.
Tumour Biol ; 41(9): 1010428319872092, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31486713

RESUMO

Angiogenesis, induced by the vascular endothelial growth factor A through its ligation to the vascular endothelial growth receptor 2, has been described as a crucial point in high-grade glioma development. The aim of this study was to evaluate the influence of VEGFA-2578C/A, -2489C/T, -1154G/A, -634G/C, and -460C/T, and KDR-604T/C, -271G/A, +1192G/A, and +1719A/T single-nucleotide polymorphisms on risk and clinicopathological aspects of high-grade glioma. This case-control study enrolled 205 high-grade glioma patients and 205 controls. Individuals with VEGFA-2578 CC or CA, VEGFA-1154 GG, VEGFA-634 GC or CC, and VEGFA-460 CT or TT genotypes were under 2.56, 1.53, 1.54, and 1.84 increased risks of high-grade glioma, compared to others, respectively. And 1.61, 2.66, 2.52, 2.53, and 2.02 increased risks of high-grade glioma were seen in individuals with VEGFA-2578 CC plus VEGFA-1154 GG, VEGFA-2578 CC or CA plus VEGFA-634 GC or CC, VEGFA-2578 CC or CA plus VEGFA-460 CT or TT, VEGFA-1154 GG or GA plus VEGFA-634 GC or CC, and VEGFA 634 GC or CC plus VEGFA-460 CT or TT combined genotypes, respectively, when compared to others. The "CAGT" haplotype of KDR single-nucleotide polymorphisms was more common in patients with grade IV than in those with grade III tumors, and individuals carrying this haplotype were at 1.76 increased risk of developing grade IV tumors than others. We present, for the first time, preliminary evidence that VEGFA-2578C/A and VEGFA-1154G/A single-nucleotide polymorphisms increases high-grade glioma risk, and "CAGT" haplotype of the KDR gene alters high-grade glioma aggressiveness and risk of grade IV tumors in Brazil.


Assuntos
Glioma/genética , Haplótipos , Polimorfismo de Nucleotídeo Único , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Fatores de Risco , Adulto Jovem
2.
Adv Clin Exp Med ; 28(9): 1179-1183, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31414734

RESUMO

BACKGROUND: Hox transcript antisense intergenic RNA (HOTAIR) is upregulated and associated with a poor prognosis in many cancer types. Besides, it is involved in the invasion and metastasis of non-small-cell lung cancer and nasopharyngeal carcinoma. OBJECTIVES: The aim of this study was to investigate the association between the expression of HOTAIR and the grades of gliomas, and to explore its possible mechanism, as well as to evaluate the value of HOTAIR applied in predicting the grades of gliomas. MATERIAL AND METHODS: A total of 123 patients undergoing glioma surgeries were enrolled. Patients with grade I and grade II-IV tumors were regarded as the control group (n = 36) and the case group (n = 87), respectively. The expression of HOTAIR, matrix metalloproteinase 7 (MMP-7), matrix metalloproteinase 9 (MMP-9), and vascular endothelial growth factor (VEGF) was detected with quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in glioma tissues and then compared between grade I and grades II-IV. The correlation between the relative expression of HOTAIR and that of MMP-7, MMP-9 and VEGF was analyzed. Multivariate analysis was performed to identify independent risk factors. Receiver operating characteristic (ROC) curve was employed to evaluate the predictive value. RESULTS: The relative expression of HOTAIR, MMP-7, MMP-9, and VEGF was lower in glioma tissues of grade I than in the case of grades II-IV, and the relative expression of HOTAIR was positively correlated with the relative expression of MMP-7, MMP-9 and VEGF. Multivariate analysis showed that the relative expression of HOTAIR was independently associated with the grades of gliomas, but the relative expression of MMP-7, MMP-9 and VEGF was not. Besides, multivariate analysis showed that the expression level of HOTAIR >0.40 was an independent risk factor for grades II-IV after classifying the relative expression of HOTAIR, and ROC analysis showed that the expression level of HOTAIR >0.40 had a moderate value when applied in predicting grades II-IV. CONCLUSIONS: Hox transcript antisense intergenic RNA might promote the invasion of gliomas through upregulating the expression of MMP-7, MMP-9 and VEGF, and the expression level of HOTAIR >0.40 had a moderate value when applied in predicting grades II-IV.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Glioma , Neoplasias Pulmonares , RNA Longo não Codificante/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/patologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Fator A de Crescimento do Endotélio Vascular
3.
Medicine (Baltimore) ; 98(27): e16205, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277128

RESUMO

With the advances in sequencing technologies and genome-wide association studies (GWAS), several inherited variants that increase glioma risk have been identified. Ten studies including 8818 cases and 17,551 controls were collected to conduct a meta-analysis to evaluate the associations between 6 variants in 8q24 and glioma risk. Of the 6 variants located in 8q24, 2 have strong significant associations with the risk of glioma, including rs4295627 (P = .003, odds ratio [OR] = 1.21), rs55705857 (P = 2.31 × 10, OR = 3.54). In particular, both homozygous GG (P = 1.91 × 10, OR1 = 2.01) and heterozygous GT (P = 7.75 × 10, OR2 = 1.35) genotypes of rs4295627 were associated with glioma risk. Further studies are needed to explore the role of the 8q24 variants involved in the etiology of glioma.


Assuntos
Neoplasias Encefálicas/genética , Cromossomos Humanos Par 8/genética , Estudo de Associação Genômica Ampla/métodos , Glioma/genética , Polimorfismo de Nucleotídeo Único , Alelos , Predisposição Genética para Doença , Genótipo , Humanos , Fatores de Risco
4.
BMC Bioinformatics ; 20(1): 396, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31315558

RESUMO

BACKGROUND: Since the number of known lncRNA-disease associations verified by biological experiments is quite limited, it has been a challenging task to uncover human disease-related lncRNAs in recent years. Moreover, considering the fact that biological experiments are very expensive and time-consuming, it is important to develop efficient computational models to discover potential lncRNA-disease associations. RESULTS: In this manuscript, a novel Collaborative Filtering model called CFNBC for inferring potential lncRNA-disease associations is proposed based on Naïve Bayesian Classifier. In CFNBC, an original lncRNA-miRNA-disease tripartite network is constructed first by integrating known miRNA-lncRNA associations, miRNA-disease associations and lncRNA-disease associations, and then, an updated lncRNA-miRNA-disease tripartite network is further constructed through applying the item-based collaborative filtering algorithm on the original tripartite network. Finally, based on the updated tripartite network, a novel approach based on the Naïve Bayesian Classifier is proposed to predict potential associations between lncRNAs and diseases. The novelty of CFNBC lies in the construction of the updated lncRNA-miRNA-disease tripartite network and the introduction of the item-based collaborative filtering algorithm and Naïve Bayesian Classifier, which guarantee that CFNBC can be applied to predict potential lncRNA-disease associations efficiently without entirely relying on known miRNA-disease associations. Simulation results show that CFNBC can achieve a reliable AUC of 0.8576 in the Leave-One-Out Cross Validation (LOOCV), which is considerably better than previous state-of-the-art results. Moreover, case studies of glioma, colorectal cancer and gastric cancer demonstrate the excellent prediction performance of CFNBC as well. CONCLUSIONS: According to simulation results, due to the satisfactory prediction performance, CFNBC may be an excellent addition to biomedical researches in the future.


Assuntos
Doença/genética , RNA Longo não Codificante/metabolismo , Algoritmos , Teorema de Bayes , Neoplasias Colorretais/genética , Simulação por Computador , Glioma/genética , Humanos , MicroRNAs/metabolismo , Neoplasias Gástricas/genética
5.
Pan Afr Med J ; 32: 197, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31312309

RESUMO

Introduction: Just recently, it has been established that the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism is linked to the pathogenesis and to the evolution of human cancers. Therefore, the present study was concerned with the investigation of an eventual association between glioma and I/D polymorphism of the ACE gene. Methods: The expression of ACE gene was detected by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis in 36 Algerian patients with glioma and 195 healthy controls. Results: In glioma cases, allelic frequencies and genotypes distribution of the ACE I/D polymorphism were different from controls cases. ACE DD genotype were highly presented in glioma cases (63.9%) than controls (33.8%) and conferred 3.64-fold risk for predisposition in glioma cases (vs ID genotype, p<0.001). Recessive model (ACE II + ID genotypes vs DD) was associated with a 72% reduced risk of glioma (OR = 0.28, 95% CI: 0.13-0.60, p <0.001). Per copy D allele frequency was found higher in glioma cases (79.2%) than in controls (63.3 %), OR = 2.20, 95% CI: 1.20 - 4.03, p = 0.009. Conclusion: The obtained data showed that the presence of the D allele might be a risk factor for the development of glioma. Further studies considering different ethnic groups with large samples are required to confirm this finding.


Assuntos
Neoplasias Encefálicas/genética , Predisposição Genética para Doença , Glioma/genética , Peptidil Dipeptidase A/genética , Adulto , Argélia , Estudos de Casos e Controles , Feminino , Deleção de Genes , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Fatores de Risco
6.
Gene ; 715: 144012, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31357021

RESUMO

Long noncoding RNAs (lncRNAs) have been shown to play an important role in tumor biogenesis and prognosis. The glioma is a grade classified cancer, however, we still lack the knowledge on their function during glioma progression. While previous studies have shown how lncRNAs regulate protein-coding gene epigenetically, it is still unclear how lncRNAs are regulated epigenetically. In this study, we firstly analyzed the RNA-seq data systematically across grades II, IV, and IV of glioma samples. We identified 60 lncRNAs that are significantly differentially expressed over disease progression (DElncRNA), including well-known PVT1, HOTAIR, H19 and rarely studied CARD8-AS, MIR4435-2HG. Secondly, by integrating HM450K methylation microarray data, we demonstrated that some of the lncRNAs are epigenetically regulated by methylation. Thirdly, we developed a DESeq2-GSEA-ceRNA-survival analysis strategy to investigate their functions. Particularly, MIR4435-2HG is highly expressed in high-grade glioma and may have an impact on EMT and TNFα signaling pathway by functioning as a miRNA sponge of miR-125a-5p and miR-125b-5p to increase the expression of CD44. Our results revealed the dynamic expression of lncRNAs in glioma progression and their epigenetic regulation mechanism.


Assuntos
Metilação de DNA , DNA de Neoplasias , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Glioma , MicroRNAs , RNA Longo não Codificante , RNA Neoplásico , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Perfilação da Expressão Gênica , Glioma/genética , Glioma/metabolismo , Glioma/patologia , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética
7.
Eur J Radiol ; 116: 174-179, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31153561

RESUMO

PURPOSE: To evaluate any possible correlation between the presence of Isocitrate DeHydrogenase 1 mutation (IDH1m) and specific DTI (Diffusion Tensor Imaging) metrics, such as Fractional Anisotropy (FA), Mean Diffusivity (MD), Radial Diffusivity (RD) and Axial Diffusivity (AD). METHODS: We retrospectively analyzed 47 patients who underwent an advanced-MR study with DTI followed by surgical intervention with a subsequent histologic diagnosis of High-Grade Glioma (HGG) and immunohistochemical evaluation of IDH1 (Isocitrate DeHydrogenase) mutation status. For each DTI metrics we measured the ratio between tumor and normal tissue and we evaluated the correlation with IDH1 mutation. RESULTS: We observed a positive correlation with IDH1 status and RD and MD data. No correlation was demonstrated between IDH1 status and FA and AD. DISCUSSION: Our results support the hypothesis that the number of residual axonal fibers, extracellular matrix composition and the presence of colliquated tissue, may together contribute to a global RD increase in HGG, with a relatively higher increase in IDH1m tumors. CONCLUSIONS: Our data are in favor of a need for multimodal advance evaluation of HGG. DTI metrics help to analyze IDH1 mutation status, in order to better characterize the lesions and to tailor treatment and follow up.


Assuntos
Glioma/patologia , Isocitrato Desidrogenase/genética , Mutação/genética , Adulto , Idoso , Anisotropia , Imagem de Tensor de Difusão/métodos , Feminino , Glioma/genética , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Estudos Retrospectivos
8.
Gen Physiol Biophys ; 38(4): 295-304, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31241046

RESUMO

Glioma is a serious malignant tumor without effective therapies till now. lncRNA PEG10 was reported to have some biological activities in cancers. Hence, we explored the effects of PEG10 on the human glioma cell line U251 cells. U251 cells were transfected with sh-PEG10 and/or miR-506 inhibitor. The expression of PEG10 and miR-506 was measured by qRT-PCR. Cell viability, cell apoptosis, cell migration and invasion were detected by CCK-8 assay, flow cytometry and Transwell chamber assay, respectively. The cell proliferation and apoptosis related p16, p53, Bcl-2, Bax, and pro-/Cleaved-Caspase-3/9, migration and invasion related-protein: matrix metalloproteinases MMP-2, MMP-9 and vimentin, and Raf/MEK/ERK and JAK1/STAT3 pathways-related proteins were accessed by Western blot. Transfection with sh-PEG10 inhibited cell viability, migration and invasion, and increased cell apoptosis. Meanwhile, PEG10 silence upregulated the expression of p16 and p53, Bax, cleaved-Caspase-3/9 expression, and downregulated Bcl-2 expression. PEG10 silence upregulated miR-506 expression. Co-transfection with sh-PEG10 and miR-506 inhibitor impaired the tumor suppressive effects. PEG10 knockdown decreased the phosphorylation of Raf/MEK/ERK and JAK1/STAT3-related proteins Raf, MEK, ERK, JAK1 and STAT3. PEG10 knockdown inhibited cell viability, migration and invasion, induced cell apoptosis through miR-506 upregulation, as well as inactivation of Raf/MEK/ERK and JAK1/STAT3 signal pathways.


Assuntos
Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glioma/patologia , MicroRNAs/genética , Invasividade Neoplásica/genética , Proteínas/genética , RNA Longo não Codificante/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Glioma/genética , Humanos , MicroRNAs/biossíntese
9.
Int J Oncol ; 55(1): 59-68, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180529

RESUMO

The present study investigated the effects of the combined treatment of two peptide nucleic acids (PNAs), directed against microRNAs involved in caspase­3 mRNA regulation (miR­155­5p and miR­221­3p) in the temozolomide (TMZ)­resistant T98G glioma cell line. These PNAs were conjugated with an octaarginine tail in order to obtain an efficient delivery to treated cells. The effects of singularly administered PNAs or a combined treatment with both PNAs were examined on apoptosis, with the aim to determine whether reversion of the drug­resistance phenotype was obtained. Specificity of the PNA­mediated effects was analyzed by reverse transcription­quantitative polymerase­chain reaction, which demonstrated that the effects of R8­PNA­a155 and R8-PNA-a221 anti­miR PNAs were specific. Furthermore, the results obtained confirmed that both PNAs induced apoptosis when used on the temozolomide­resistant T98G glioma cell line. Notably, co­administration of both anti­miR­155 and anti­miR­221 PNAs was associated with an increased proapoptotic activity. In addition, TMZ further increased the induction of apoptosis in T98G cells co­treated with anti­miR­155 and anti­miR­221 PNAs.


Assuntos
Caspase 3/metabolismo , Glioma/tratamento farmacológico , Glioma/genética , MicroRNAs/antagonistas & inibidores , Ácidos Nucleicos Peptídicos/farmacologia , Temozolomida/farmacologia , Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Glioma/enzimologia , Humanos , MicroRNAs/genética , Ácidos Nucleicos Peptídicos/genética
10.
BMC Neurol ; 19(1): 134, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31215432

RESUMO

BACKGROUND: CIC-mutant oligodendroglial tumours linked to better prognosis. We aim to investigate associations between CIC gene mutation status, MR characteristics and clinical features. METHODS: Imaging and genomic data from the Cancer Genome Atlas and the Cancer Imaging Archive (TCGA/TCIA) for 59 patients with oligodendroglial tumours were used. Differences between CIC mutation and CIC wild-type were tested using Chi-square test and binary logistic regression analysis. RESULTS: In univariate analysis, the clinical variables and MR features, which consisted 3 selected features (subventricular zone[SVZ] involvement, volume and seizure history) were associated with CIC mutation status (all p < 0.05). A multivariate logistic regression analysis identified that seizure history (no vs. yes odd ratio [OR]: 28.960, 95 confidence interval [CI]:2.625-319.49, p = 0.006) and SVZ involvement (SVZ- vs. SVZ+ OR: 77.092, p = 0.003; 95% CI: 4.578-1298.334) were associated with a higher incidence of CIC mutation status. The nomogram showed good discrimination, with a C-index of 0.906 (95% CI: 0.812-1.000) and was well calibrated. SVZ- group has increased (SVZ- vs. SVZ+, hazard ratio [HR]: 4.500, p = 0.04; 95% CI: 1.069-18.945) overall survival. CONCLUSIONS: Absence of seizure history and SVZ involvement (-) was associated with a higher incidence of CIC mutation.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioma/genética , Glioma/patologia , Proteínas Repressoras/genética , Adulto , Idoso , Neoplasias Encefálicas/complicações , Feminino , Glioma/complicações , Humanos , Ventrículos Laterais/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Modelos de Riscos Proporcionais , Convulsões/etiologia
11.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(5): 566-571, 2019 May 30.
Artigo em Chinês | MEDLINE | ID: mdl-31140421

RESUMO

OBJECTIVE: To investigate the inhibitory effects of silencing migration-inducing gene-7 (Mig-7) on vasculogenic mimicry formation, migration and invasion of human glioma cells in vitro and whether MEK/ERK signaling pathway mediates these effects. METHODS: Human glioma U251 cells were infected by lentiviral vectors carrying a small interfering RNA targeting Mig-7 gene (sh-Mig-7) or a negative control shRNA (sh-NC), and real-time quantitative PCR was used to detect the expression level of Mig-7 mRNA in the cells. Three-dimensional culture and Transwell chamber invasion assay were used to observe the effect of Mig-7 gene silencing on vasculogenic mimicry formation and invasion ability of the U251 cells. Western blotting was performed to detect the changes in the protein expression levels of MEK/ERK in the infected cells. RESULTS: We successfully obtained a U251 cell line with stable low expression of Mig-7 gene using RNA interference technique. Compared with the cells infected with sh-NC lentivirus and the non- infected cells, U251 cells infected with the lentiviral vector carrying sh-Mig-7 showed significantly decreased expression level of Mig-7 (P < 0.01) with obviously lowered vasculogenic mimicry formation and invasion abilities (P < 0.05). Mig-7 silencing also significantly lowered the expressions of MEK and ERK proteins in U251 cells (P < 0.05). CONCLUSIONS: Silencing of Mig-7 gene inhibits vasculogenic mimicry formation and invasion of U251 cells possibly by suppressing MEK/ERK signaling, suggesting the important role of Mig-7 gene in vasculogenic mimicry formation and invasion of human glioma cells.


Assuntos
Inativação Gênica , Glioma , Proteínas de Neoplasias , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Glioma/genética , Glioma/patologia , Humanos , Proteínas de Neoplasias/metabolismo , RNA Interferente Pequeno , Transdução de Sinais
12.
Nat Commun ; 10(1): 2146, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086175

RESUMO

Posterior fossa type A (PFA) ependymomas exhibit very low H3K27 methylation and express high levels of EZHIP (Enhancer of Zeste Homologs Inhibitory Protein, also termed CXORF67). Here we find that a conserved sequence in EZHIP is necessary and sufficient to inhibit PRC2 catalytic activity in vitro and in vivo. EZHIP directly contacts the active site of the EZH2 subunit in a mechanism similar to the H3 K27M oncohistone. Furthermore, expression of H3 K27M or EZHIP in cells promotes similar chromatin profiles: loss of broad H3K27me3 domains, but retention of H3K27me3 at CpG islands. We find that H3K27me3-mediated allosteric activation of PRC2 substantially increases the inhibition potential of EZHIP and H3 K27M, providing a mechanism to explain the observed loss of H3K27me3 spreading in tumors. Our data indicate that PFA ependymoma and DIPG are driven in part by the action of peptidyl PRC2 inhibitors, the K27M oncohistone and the EZHIP 'oncohistone-mimic', that dysregulate gene silencing to promote tumorigenesis.


Assuntos
Neoplasias Encefálicas/genética , Ependimoma/genética , Glioma/genética , Proteínas Oncogênicas/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Animais , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Linhagem Celular Tumoral , Cromatina/metabolismo , Ilhas de CpG , Fossa Craniana Posterior , Conjuntos de Dados como Assunto , Embrião de Mamíferos , Ependimoma/patologia , Fibroblastos , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Glioma/patologia , Células HEK293 , Histonas , Humanos , Camundongos , Proteínas Oncogênicas/genética , Cultura Primária de Células , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo
13.
Pathobiology ; 86(2-3): 152-161, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31096221

RESUMO

INTRODUCTION: The interaction of K27M mutation in histone H3 (H3K27M mutation) with polycomb repressive complex 2 (PRC2) is facilitated by the enhancer of zeste homolog 2 (EZH2). Subsequently, this interaction leads to the global reduction level of H3K27me3. We analyzed the EZH2 expression level in H3K27M mutation-positive tumors and revealed the association of high EZH2 expression with poor survival. METHODS: Our study included 12 patients, with an age range of 6-56 years and treated between 2007 and 2016. All patients underwent MRI study for nonenhanced T1, T2, diffusion, gadolinium-enhanced T1-weighted imaging, and fluid-attenuated inversion recovery (FLAIR). Immunohistochemical staining was performed against H3K27M, H3K27me3, EZH2, EED, mutant isocitrate dehydrogenase 1 (IDH1), α-thalassemia X-linked intellectual disability (ATRX), p53, O6-methylguanine-DNA methyltransferase (MGMT), and Ki-67 antibodies. RESULTS: All patients were negative for IDH1R132H and H3K27me3, but H3K27M-positive. Staining against EZH2 was negative in all histological features of grade II cases (3/12) and positive in grade III and IV cases; EZH2 positivity is associated with poor prognosis (p = 0.0082). EZH2 positivity was not associated with EED positivity. Retained ATRX staining was found mostly in grade III and IV cases (6/12). P53 was predominantly positive in cases of astrocytoma and glioblastoma (8/12). The labeling index of Ki-67 was 1.2-31.4% for grade II and III histological features and 11.2-24.8% for grade IV. CONCLUSION: We suggest that the expression of EZH2 is not associated with the PRC2 pathway and increases in patients with H3K27M-mutant diffuse midline glioma and a poor prognosis. Further studies are necessary to understand the mechanism involved.


Assuntos
Neoplasias Encefálicas/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Glioma/genética , Mutação , Adolescente , Adulto , Neoplasias Encefálicas/diagnóstico , Criança , Feminino , Glioma/diagnóstico , Histonas/genética , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Complexo Repressor Polycomb 2/genética , Prognóstico , Coloração e Rotulagem , Análise de Sobrevida , Adulto Jovem
14.
J Exp Clin Cancer Res ; 38(1): 184, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053160

RESUMO

BACKGROUND: Celastrol, a triterpene compound derived from the traditional Chinese medicine Tripterygium wilfordii, has been reported to possess potential antitumor activity towards various malignancies. However, the effect of celastrol on glioma cells and the underlying molecular mechanisms remain elusive. METHODS: Glioma cells, including the U251, U87-MG and C6 cell lines and an animal model were used. The effects of celastrol on cells were evaluated by flow cytometry, confocal microscopy, reactive oxygen species production assay and immunoblotting after treatment of celastrol. Fisher's exact test, a one-way ANOVA and the Mann-Whitney U-test were used to compare differences between groups. All data were analyzed using SPSS version 21.0 software. RESULTS: Here, we found that exposure to celastrol induced G2/M phase arrest and apoptosis. Celastrol increased the formation of autophagosomes, accumulation of LC3B and the expression of p62 protein. Celastrol-treated glioma cells exhibited decreased cell viability after the use of autophagy inhibitors. Additionally, autophagy and apoptosis caused by celastrol in glioma cells inhibited each other. Furthermore, celastrol induced JNK activation and ROS production and inhibited the activities of Akt and mTOR kinases. JNK and ROS inhibitors significantly attenuated celastrol-trigged apoptosis and autophagy, while Akt and mTOR inhibitors had opposite effects. CONCLUSIONS: In conclusion, our study revealed that celastrol caused G2/M phase arrest and trigged apoptosis and autophagy by activating ROS/JNK signaling and blocking the Akt/mTOR signaling pathway.


Assuntos
Glioma/tratamento farmacológico , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Serina-Treonina Quinases TOR/genética , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Autofagossomos/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glioma/genética , Glioma/patologia , Humanos , MAP Quinase Quinase 4/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-myc/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Anticancer Res ; 39(5): 2299-2306, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092421

RESUMO

BACKGROUND/AIM: Death receptor 6 (DR6) is a member of the tumor necrosis factor receptor superfamily. The expression of DR6 is elevated in different kinds of tumors including ovarian, breast cancer and adult sarcoma. In these tumors, the receptor may be handled as a new diagnostic and prognostic marker. Thus, we investigated the expression of DR6 in gliomas. MATERIALS AND METHODS: Tumor and control tissues were extracted during neurosurgery and grouped according to the WHO classification. DR6 expression was investigated in low- and high-grade gliomas PCR (n=70), immunofluorescence staining (n=33) and western blot (n=58). Additional analysis of TCGA-data was performed to assess the general alteration of DR6 in cancer and influence of IDH-mutation on DR6 expression in gliomas. RESULTS: The expression of DR6 was significantly enhanced in gliomas (p<0.05). It showed a trend towards rising expression with increasing malignancy of the tumor. Chemotherapy treatment could have an influence on DR6 expression. CONCLUSION: In our investigation, DR6 acts as a potential suitable diagnostic marker for gliomas.


Assuntos
Astrocitoma/genética , Biomarcadores Tumorais/genética , Glioma/genética , Receptores do Fator de Necrose Tumoral/genética , Astrocitoma/tratamento farmacológico , Astrocitoma/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/tratamento farmacológico , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Masculino , Mutação , Gradação de Tumores
16.
Med Sci Monit ; 25: 2583-2590, 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30962415

RESUMO

Glioblastoma multiforme (GBM) is the most common primary CNS cancer and has a poor prognosis. This study searched for significant genes and the mechanisms involved in GBM. We used the Gene Expression Omnibus (GEO) to test the WHO normal and IV glioma database, used R tool to identify the significant gene, and finally, combined these with The Cancer Genome Atlas (TCGA) to verify the significant genes. Subsequently, we explored the biological mechanisms involved. Phytanoyl-CoA 2-hydroxylase-interacting protein-like gene (PHYHIPL) is downregulated in grade IV glioma (GBM). The downregulation of PHYHIPL in GBM is accompanied by poor overall survival in the TCGA database, which indicates that PHYHIPL is a protection gene in GBM development. Bioinformatics analysis shows that the poor prognosis with downregulated PHYHIPL may be the result of the TNF signaling pathway and the IL-17 signaling pathway, but good prognosis accompanied by upregulated PHYHIPL may be the result of retrograde endocannabinoid signaling and the cAMP signaling pathway. Protein-protein interactions (PPI) net indicated that PHYHIPL may play a vital role in cell metabolism, and we hypothesize that the downregulation mechanism may be the result of mutations of the ß-catenin gene and the endogenous siRNA, as shown in previous studies. PHYHIPL may be a target gene for the treatment and prognosis of GBM.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Glioblastoma/genética , Glioblastoma/terapia , Proteínas do Tecido Nervoso/metabolismo , Coenzima A/genética , Coenzima A/metabolismo , Biologia Computacional/métodos , Bases de Dados Genéticas , Redes Reguladoras de Genes/genética , Glioma/genética , Humanos , Mutação/genética , Ácido Fitânico/análogos & derivados , Ácido Fitânico/metabolismo , Prognóstico , Transdução de Sinais
17.
Eur J Radiol ; 114: 152-159, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31005167

RESUMO

PURPOSE: H3 K27M-mutant diffuse midline gliomas are associated with worse prognosis than H3 K27M wild-type gliomas. In the present study, we sought to evaluate the conventional magnetic resonance imaging (cMRI) of H3 K27M-mutant glioma and examine whether diffusion-weighted imaging (DWI) derived apparent diffusion coefficient (ADC) could noninvasively predict H3 K27M mutational status in brain diffuse midline gliomas. MATERIALS AND METHODS: The institutional review board approved this study and waived the requirement for informed consent. Thirty-eight patients with brain diffuse midline gliomas were retrospectively reviewed. The parameters of preoperative cMRI were evaluated. The minimal ADC, peritumoral ADC, ratio of minimal ADC, and ratio of peritumoral ADC were measured, and significant differences between the two groups were identified by logistic regression analysis adjusted for age and tumor location. Receiver operating characteristic curves and logistic regression analysis adjusted for age and tumor location were used to assess the diagnostic performances of the minimal ADC, peritumoral ADC, ratio of minimal ADC, and ratio of peritumoral ADC. RESULTS: H3 K27M-mutant gliomas in different locations have diverse imaging characteristics. Minimal ADC, peritumoral ADC, ratio of minimal ADC, and ratio of peritumoral ADC values were significantly lower in the H3 K27M-mutant gliomas than in the wild-type gliomas (P < 0.05). The combination of ratio of minimal ADC and ratio of peritumoral ADC provided the largest area under the curve (AUC) of 0.872 in defining H3 K27M-mutational status. CONCLUSIONS: The combination of ratio of minimal ADC and ratio of peritumoral ADC can noninvasively detect the H3 K27M mutational status in brain diffuse midline gliomas.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Imagem de Difusão por Ressonância Magnética , Glioma/diagnóstico por imagem , Glioma/genética , Histonas/genética , Mutação/genética , Adolescente , Adulto , Neoplasias Encefálicas/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Gradação de Tumores , Valor Preditivo dos Testes , Estudos Retrospectivos , Adulto Jovem
18.
J Cancer Res Ther ; 15(2): 358-364, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30964111

RESUMO

Objective: The objective of the study is to evaluate levels of chemokine (C-C motif) ligand 18 (CCL18) in human glioma tissues and effects of CCL18 on U251 glioma cells. Materials and Methods: By using the real-time reverse transcription polymerase chain reaction and immunochemically histological staining, we determined the mRNA and protein levels of CCL18 in tissues of 60 patients with World Health Organization (WHO) Grades II, III and IV glioma and the normal brain. Cultured U251 glioma cells were incubated with CCL18 and then subjected to transwell. The scratch wound-healing and cell count kit (CCK-8) assays were performed to detect the possible effects of CCL18 on the cell invasion, migration, and proliferation. Results: In the tissues of the normal brain (n = 10), glioma Grade II (n = 26), III (n = 18), and IV (n = 16), CCL18 mRNA expression levels were 1.00 ± 0.09, 6.02 ± 1.26, 26.35 ± 3.98, and 112.21 ± 13.25 fold, respectively (P < 0.01); the percentage of CCL18-positive glioma cells was 0%, 58.8%, 70.0%, and 100% in the normal brain, glioma WHO Grade II, III, and IV, respectively (P < 0.01). Different concentrations of CCL18 (0, 5, and 10 ng/ml) enhanced the of U251 glioma cell invasion in 24 h transwell assays [from 43.5 ± 8.3 to 202.0 ± 18.5 and 279.7 ± 18.6 cells (P < 0.01)], increased the cell migration quantified by comparing the areas of the scratch (pixel) [at 12 h, 498.4 ± 75.3, 381.3 ± 21.4, and 347.7 ± 14.2; at 24 h, 299.5 ± 15.3, 284.6 ± 7.8, and 237.3 ± 20.6 (P < 0.05)], and significantly increased the cell growth in CCK-8 assay [from 1.000 ± 0.019-1.260 ± 0.094 and 2.070 ± 0.138 fold in CCL18, respectively (n = 20/each group) (P < 0.01)]. Conclusion: We have found that CCL18 is highly expressed in glioma tissues and enhances the invasion, migration, and proliferation of U251 glioma cells. Therefore, CCL18 may be a potential biomarker for detecting and grading human glioma.


Assuntos
Quimiocinas CC/genética , Expressão Gênica , Glioblastoma/genética , Glioma/genética , Adulto , Biomarcadores , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Quimiocinas CC/metabolismo , Feminino , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioma/metabolismo , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , RNA Mensageiro/genética , Carga Tumoral , Adulto Jovem
19.
Pathologe ; 40(Suppl 1): 9-17, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31025086

RESUMO

BACKGROUND: Diffuse astrocytic and oligodendroglial gliomas are the most common neuroepithelial tumors. Their classification is based on the integration of histological and molecular findings according to the classification of tumors of the central nervous system published by the World Health Organization (WHO) in 2016. OBJECTIVES: This review describes the different entities and variants of diffuse gliomas and summarizes the current diagnostic criteria for these tumors. MATERIALS AND METHODS: Based on the 2016 WHO classification and selected other publications, the histomolecular diagnostics of diffuse gliomas is presented and illustrated. RESULTS: Diffuse gliomas are divided into isocitrate dehydrogenase (IDH)-mutant or IDH-wildtype gliomas by detection of mutations in the IDH1 or IDH2 genes. Among the IDH-mutant gliomas, oligodendroglial tumors are characterized by combined losses of chromosome arms 1p and 19q. Loss of nuclear expression of the ATRX protein is a marker of IDH- mutant astrocytic gliomas. Glioblastoma, IDH-wildtype, is the most common diffuse glioma. Diffuse and anaplastic astrocytic gliomas without IDH mutation should be further evaluated for molecular features of glioblastoma, IDH-wildtype. Diffuse gliomas in the thalamus, brainstem, or spinal cord carrying a histone 3 (H3)-K27M mutation are classified as diffuse midline gliomas, H3-K27M-mutant. By determining the IDH and 1p/19q status, oligoastrocytomas can be stratified into either astrocytic or oligodendroglial gliomas. Gliomatosis cerebri is no longer regarded as a distinct glioma entity. CONCLUSIONS: Diffuse gliomas can today be classified accurately and reproducibly by means of histological, immunohistochemical, and molecular analyses.


Assuntos
Astrócitos/patologia , Neoplasias Encefálicas/diagnóstico , Glioma/diagnóstico , Oligodendroglioma/patologia , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioma/enzimologia , Glioma/genética , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Mutação , Proteína Nuclear Ligada ao X/metabolismo
20.
J Exp Clin Cancer Res ; 38(1): 147, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953555

RESUMO

BACKGROUND: Ionizing radiation (IR) therapy is the standard first-line treatment for newly diagnosed patients with glioblastoma (GBM), the most common and malignant primary brain tumor. However, the effects of IR are limited due to the aberrant radioresistance of GBM. METHODS: Transcriptome analysis was performed using RNA-seq in radioresistant patient-derived glioma stem-like cells (GSCs). Survival of glioma patient and mice bearing-brain tumors was analyzed by Kaplan-Meier survival analysis. Lipid droplet and γ-H2AX foci-positive cells were evaluated using immunofluorescence staining. RESULTS: Lipolytic inhibitor G0/G1 switch gene 2 (G0S2) is upregulated in radioresistant GSCs and elevated in clinical GBM. GBM patients with high G0S2 expression had significantly shorter overall survival compared with those with low expression of G0S2. Using genetic approaches targeting G0S2 in glioma cells and GSCs, we found that knockdown of G0S2 promoted lipid droplet turnover, inhibited GSC radioresistance, and extended survival of xenograft tumor mice with or without IR. In contrast, overexpression of G0S2 promoted glioma cell radiation resistance. Mechanistically, high expression of G0S2 reduced lipid droplet turnover and thereby attenuated E3 ligase RNF168-mediated 53BP1 ubiquitination through activated the mechanistic target of rapamycin (mTOR)-ribosomal S6 kinase (S6K) signaling and increased 53BP1 protein stability in response to IR, leading to enhanced DNA repair and glioma radioresistance. CONCLUSIONS: Our findings uncover a new function for lipolytic inhibitor G0S2 as an important regulator for GSC radioresistance, suggesting G0S2 as a potential therapeutic target for treating gliomas.


Assuntos
Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular/genética , Glioma/genética , Tolerância a Radiação/fisiologia , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular , Glioma/patologia , Humanos , Camundongos , Transfecção
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