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1.
Gene ; 723: 144126, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31589963

RESUMO

Non-coding RNAs are known to participate in cancer initiation, progression, and metastasis by regulating the status of chromatin epigenetics and gene expression. Although these non-coding RNAs do not possess defined protein-coding potential, they are involved in the expression and stability of messenger RNA (mRNA). The length of microRNAs (miRs) ranges between 20 and 22 nt, whereas, long non-coding RNAs (lncRNAs) length ranges between 200 nt to 1 Kb. In the case of circular RNAs (circRNAs), the size varies depending upon the length of the exon from where they were derived. Epigenetic regulations of miR and lncRNA genes will influence the gene expression by modulating histone acetylation and methylation patterns. Especially, lncRNAs will act as a scaffold for various epigenetic proteins, such as EZH2 and LSD1, and influence the chromatin epigenetic state at various genomic loci involved at silencing. Thus investigations on the expression of lncRNAs and designing drugs to modulate the expression of these genes will have a profound impact on future therapeutics against cancers such as Glioblastoma Multiforme (GBM) and also against various other diseases. With the recent advancements in genome-wide transcriptomic studies, scientists are focused on the non-coding RNAs and their regulations on various cellular processes involved in GBM and on other types of cancer as well as trying to understand possible epigenetic modulations that help in generating promising therapeutics for the future generations. In this review, the involvement of epigenetic proteins, enzymes that change chromatin architecture and epigenetic landscape and new roles of lncRNAs that are involved in GBM progression are elaborately discussed.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , MicroRNAs/genética , RNA Longo não Codificante/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/genética , Ensaios Clínicos como Assunto , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Glioblastoma/genética , Humanos
2.
Life Sci ; 236: 116917, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31614149

RESUMO

AIMS: To investigate the underlying mechanism by which glioblastoma (GBM) cells gain temozolomide (TMZ) resistance and to clarify novel therapeutic targets and new prognostic biomarkers for GBM. MAIN METHODS: A genome-wide hierarchical bi-clustering based on previously published microarray databases identified Nuclear Factor I A (NFIA) as one of the most significantly upregulated genes correlated to TMZ resistance in GBM. Then, the potential biological functions of NFIA in oncogenesis and chemoresistance were clarified by qRT-PCR, Western blotting and in vivo xenograft models with artificially induced TMZ-resistant U87 cells. Additionally, immunohistochemistry (IHC) assays were performed to explore the clinical significance of NFIA in glioma patients. Last, luciferase reporter assay was performed to study the transcriptional regulation of NFIA on the nuclear factor κb (NF-kB) pathway. KEY FINDINGS: NFIA was correlated with TMZ resistance in GBM. Clinically, elevated NFIA expression was significantly correlated with adverse outcomes of glioma patients, especially in GBM patients. Moreover, NFIA contributed to the acquired TMZ resistance of GBM cells, while suppression of NFIA via lentivirus reduced cell proliferation, tumorigenesis and resistance to TMZ of GBM. Additionally, NFIA promoted transcription activity that regulated the expression of NF-kB. Last, NFIA induced phosphorylation of NF-kB p65 at serine 536, thus inducing TMZ resistance in GBM cells. Altogether, our study suggests that NFIA-dependent transcriptional regulation of NF-kB contributes to acquired TMZ resistance in GBM. SIGNIFICANCE: Abnormally activated NFIA-NF-kB signaling was strongly correlated with acquired TMZ resistance and poor prognosis in GBM, and it could be a new therapeutic target for TMZ-resistant GBM.


Assuntos
Neoplasias Encefálicas/patologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/patologia , NF-kappa B/metabolismo , Fatores de Transcrição NFI/metabolismo , Temozolomida/farmacologia , Animais , Antineoplásicos Alquilantes/farmacologia , Apoptose , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Camundongos , Camundongos Nus , NF-kappa B/genética , Fatores de Transcrição NFI/genética , Prognóstico , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Cancer Treat Rev ; 80: 101896, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31541850

RESUMO

Glioblastomas are intrinsic brain tumors thought to originate from neuroglial stem or progenitor cells. More than 90% of glioblastomas are isocitrate dehydrogenase (IDH)-wildtype tumors. Incidence increases with age, males are more often affected. Beyond rare instances of genetic predisposition and irradiation exposure, there are no known glioblastoma risk factors. Surgery as safely feasible followed by involved-field radiotherapy plus concomitant and maintenance temozolomide chemotherapy define the standard of care since 2005. Except for prolonged progression-free, but not overall survival afforded by the vascular endothelial growth factor antibody, bevacizumab, no pharmacological intervention has been demonstrated to alter the course of disease. Specifically, targeting cellular pathways frequently altered in glioblastoma, such as the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), the p53 and the retinoblastoma (RB) pathways, or epidermal growth factor receptor (EGFR) gene amplification or mutation, have failed to improve outcome, likely because of redundant compensatory mechanisms, insufficient target coverage related in part to the blood brain barrier, or poor tolerability and safety. Yet, uncommon glioblastoma subsets may exhibit specific vulnerabilities amenable to targeted interventions, including, but not limited to: high tumor mutational burden, BRAF mutation, neurotrophic tryrosine receptor kinase (NTRK) or fibroblast growth factor receptor (FGFR) gene fusions, and MET gene amplification or fusions. There is increasing interest in targeting not only the tumor cells, but also the microenvironment, including blood vessels, the monocyte/macrophage/microglia compartment, or T cells. Improved clinical trial designs using pharmacodynamic endpoints in enriched patient populations will be required to develop better treatments for glioblastoma.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Reposicionamento de Medicamentos , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Terapia de Alvo Molecular , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
Medicine (Baltimore) ; 98(35): e16933, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31464930

RESUMO

BACKGROUND: Previous studies have demonstrated that single-nucleotide polymorphisms (SNPs) in miRNAs are related to the susceptibility to brain tumors, but the conclusions remain controversial. This study was to perform a meta-analysis to re-assess the associations between miRNA SNPs and brain tumor risk. METHODS: Relevant studies were identified in the databases of PubMed and the Cochrane Library databases. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated to assess the relationships between SNPs and the risk of brain tumors under various genetic models by the STATA software. RESULTS: Five studies, containing 2275 cases, and 2323 controls, were included, 4 of which evaluated miR-196a2 (rs11614913), 3 for miR-146a (rs2910164) and 2 for miR-499 (rs3746444) and miR-149 (rs2292832), respectively. The meta-analysis indicated that the GG genotype carriers of miR-146a were more susceptible to brain tumors compared with GC genotype carriers (OR = 1.19, 95%CI = 1.01-1.41, P = .036). No significant associations were observed between the SNPs of other miRNAs and the risk of brain tumors. Furthermore, all miRNA polymorphisms did not show significant associations with the risk of glioma subgroup in any genetic models, while meta-analysis of non-glioma subgroup could not be performed due to low statistical power and analysis of only 1 study. CONCLUSION: Our study suggests that miR-146a polymorphism may modify the risk for brain tumors, but which type (glioma or benign non-glioma tumors) should be verified with large sample size.


Assuntos
Neoplasias Encefálicas/genética , MicroRNAs/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único
5.
BMC Bioinformatics ; 20(1): 428, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31419933

RESUMO

BACKGROUND: With the advent of array-based techniques to measure methylation levels in primary tumor samples, systematic investigations of methylomes have widely been performed on a large number of tumor entities. Most of these approaches are not based on measuring individual cell methylation but rather the bulk tumor sample DNA, which contains a mixture of tumor cells, infiltrating immune cells and other stromal components. This raises questions about the purity of a certain tumor sample, given the varying degrees of stromal infiltration in different entities. Previous methods to infer tumor purity require or are based on the use of matching control samples which are rarely available. Here we present a novel, reference free method to quantify tumor purity, based on two Random Forest classifiers, which were trained on ABSOLUTE as well as ESTIMATE purity values from TCGA tumor samples. We subsequently apply this method to a previously published, large dataset of brain tumors, proving that these models perform well in datasets that have not been characterized with respect to tumor purity . RESULTS: Using two gold standard methods to infer purity - the ABSOLUTE score based on whole genome sequencing data and the ESTIMATE score based on gene expression data- we have optimized Random Forest classifiers to predict tumor purity in entities that were contained in the TCGA project. We validated these classifiers using an independent test data set and cross-compared it to other methods which have been applied to the TCGA datasets (such as ESTIMATE and LUMP). Using Illumina methylation array data of brain tumor entities (as published in Capper et al. (Nature 555:469-474,2018)) we applied this model to estimate tumor purity and find that subgroups of brain tumors display substantial differences in tumor purity. CONCLUSIONS: Random forest- based tumor purity prediction is a well suited tool to extrapolate gold standard measures of purity to novel methylation array datasets. In contrast to other available methylation based tumor purity estimation methods, our classifiers do not need a priori knowledge about the tumor entity or matching control tissue to predict tumor purity.


Assuntos
Algoritmos , Metilação de DNA/genética , Neoplasias/genética , Análise de Sequência com Séries de Oligonucleotídeos , Software , Neoplasias Encefálicas/genética , DNA de Neoplasias , Humanos , Reprodutibilidade dos Testes
6.
Medicine (Baltimore) ; 98(33): e16766, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415376

RESUMO

Patients with non-small cell lung cancer (NSCLC) and de novo brain metastasis (BM) have poor prognosis. We aim to investigate the characteristic of brain magnetic resonance (MR) imaging and the association with the treatment response of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) for lung cancer with BM.EGFR-mutated NSCLC patients with BM from October 2013 to December 2017 in a tertiary referral center were retrospectively analyzed. Patient's age, sex, cell type, EGFR mutation status, treatment, and characteristics of BM were collected. Survival analysis was performed using Kaplan-Meier method. The efficacy of different EGFR-TKIs were also analyzed.Among the 257 eligible patients, 144 patients with Exon 19 deletion or Exon 21 L858R were included for analysis. The erlotinib group had the best progression free survival (PFS) (median PFS 13 months, P = .04). The overall survival (OS) revealed no significant difference between three EGFR-TKI groups. Brain MR imaging features including tumor necrosis, rim enhancement and specific tumor locations (frontal lobe, putamen or cerebellum) were factors associated with poor prognosis. Patients with poor prognostic imaging features, the high-risk group, who received erlotinib had the best PFS (median PFS 12 months, P < .001). However, the OS revealed no significant difference between 3 EGFR-TKI groups. The low risk group patients had similar PFS and OS treated with three different EGFR-TKIs.In NSCLC patients with common EGFR mutation and de novo BM, those with poor prognostic brain MR characteristics, erlotinib provided better PFS than afatinib or gefitinib.


Assuntos
Neoplasias Encefálicas/terapia , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Terapia Combinada , Intervalo Livre de Doença , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Valor Preditivo dos Testes , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Taiwan
7.
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
8.
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
9.
Zhonghua Yi Xue Za Zhi ; 99(25): 1959-1962, 2019 Jul 02.
Artigo em Chinês | MEDLINE | ID: mdl-31269600

RESUMO

Objective: To investigate the prognostic values of IDH, TERT and 1p/19q in patients with anaplastic oligodendroglioma. Methods: In the study, 66 patients with pathological diagnosis of anaplastic oligodendroglioma were enrolled (The First Affiliated Hospital of Zhengzhou University 2011 to 2016 years). Kaplan-Meier method was used to calculate the survival rates. Log-rank was used to calculate the differences in group. Chi-square testwas used tocalculate the differences in common factor group. Cox regression model was used to conduct multivariate analysis. Results: The median survival time of IDH-wt and IDH-mt subgroups were 16.10 and 42.00 months with statistical significance (P=0.001). The median survival time of 1p/19q codeleted and 1p/19q noncodeleted subgroups were 42.00 and 22.40 months with statistical significance (P=0.012). IDH-mt and 1p/19q codeleted predicted better survivals compared with IDH-wt and 1p/19q noncodeleted (P=0.001). And IDH-mt and 1p/19q noncodeleted predicted better survivals compared with IDH-wt and 1p/19q noncodeleted (P=0.041), too. Multivariate survival analysis demonstrated that Molecular groups was an independent factor to evaluate the prognosis of anaplastic oligodendroglioma (P=0.008). Conclusion: IDH-mtand (or) 1p/19q codeletedpredicted better survivals in patients with anaplastic oligodendroglioma. IDH and 1p/19q deleted might be a biomarker for predicting prognosis of patients with anaplastic oligodendroglioma.


Assuntos
Neoplasias Encefálicas , Isocitrato Desidrogenase/genética , Oligodendroglioma , Telomerase/genética , Adulto , Neoplasias Encefálicas/genética , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 19 , Humanos , Mutação , Oligodendroglioma/genética , Prognóstico
10.
Genes Dev ; 33(11-12): 591-609, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31160393

RESUMO

Glioblastoma ranks among the most lethal of all human cancers. Glioblastomas display striking cellular heterogeneity, with stem-like glioblastoma stem cells (GSCs) at the apex. Although the original identification of GSCs dates back more than a decade, the purification and characterization of GSCs remains challenging. Despite these challenges, the evidence that GSCs play important roles in tumor growth and response to therapy has grown. Like normal stem cells, GSCs are functionally defined and distinguished from their differentiated tumor progeny at core transcriptional, epigenetic, and metabolic regulatory levels, suggesting that no single therapeutic modality will be universally effective against a heterogenous GSC population. Glioblastomas induce a systemic immunosuppression with mixed responses to oncoimmunologic modalities, suggesting the potential for augmentation of response with a deeper consideration of GSCs. Unfortunately, the GSC literature has been complicated by frequent use of inferior cell lines and a lack of proper functional analyses. Collectively, glioblastoma offers a reliable cancer to study cancer stem cells to better model the human disease and inform improved biologic understanding and design of novel therapeutics.


Assuntos
Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/fisiopatologia , Glioblastoma/patologia , Glioblastoma/fisiopatologia , Células-Tronco Neoplásicas/fisiologia , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Diferenciação Celular , Epigênese Genética , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Microambiente Tumoral
11.
Gene ; 710: 233-239, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31181312

RESUMO

Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor. Numerous studies have demonstrated that aberrant microRNAs (miRNAs) expression is involved in various pathogenesis events in GBM. miR-454-3p has been found to be downregulated in GBM, however, the role and underlying mechanism has not been fully investigated. The expression levels of miR-454-3p in GBM clinical tissues and cultured cell lines were measured by qRT-PCR. To evaluate the role of miR-454-3p in GBM, GBM cells were transfected with miR-454-3p inhibitor (anti-miR-454-3p)/control inhibitor (anti-miR-NC) or miR-454-3p mimic/control mimic (miR-NC). Online prediction algorithm Targetscan was used to predict the target genes of miR-454-3p. The dual luciferase reporter gene assay was performed to confirm whether nuclear factor of activated T cells c2 (NFATc2) was a direct biological target of miR-454-3p. We found that miR-454-3p expression was significantly decreased in both GBM tissues and cultured cell lines. Overexpression of miR-454-3p by transfection with miR-454-3p mimic suppressed cell proliferation and induced apoptosis of GBM cells. Nuclear factor of activated T cells c2 (NFATc2) was predicted as a target gene of miR-454-3p. We found that NFATc2 expression was significantly increased in both GBM tissues and cultured cell lines. Besides, expression levels of miR-454-3p were negatively associated with NFATc2 expression in GBM tissues. NFATc2 knockdown in GBM cells obviously inhibited cell proliferation and elevated apoptosis. Luciferase reporter assay revealed that NFATc2 was a target gene of miR-454-3p. miR-454-3p overexpression suppressed the NFATc2 expression, while inhibition of miR-454-3p induced the NFATc2 expression. Suppression of NFATc2 blocked the effects of miR-454-3p inhibitor on cell proliferation and apoptosis in GBM cells. The results indicated that miR-454-3p executed the tumor suppressive activity via downregulating NFATc2 in GBM.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , MicroRNAs/genética , Fatores de Transcrição NFATC/genética , Algoritmos , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Pessoa de Meia-Idade
12.
DNA Cell Biol ; 38(7): 688-699, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31188028

RESUMO

This study was aimed to identify hub genes associated with the development of glioblastoma (GBM) by conducting a bioinformatic analysis. The raw gene expression data were downloaded from the Gene Expression Omnibus database and The Cancer Genome Atlas project. After the differentially expressed genes (DEGs) were identified, the functional enrichment analysis of DEGs was conducted. Subsequently, the protein-protein interaction (PPI) network, molecular complex detection clusters, and transcriptional factor (TF)-miRNA-target regulatory network were constructed, respectively. Furthermore, the survival analysis of prognostic outcomes and genes was analyzed. In addition, the expression of key genes was validated by quantitative real-time PCR (qRT-PCR) analysis. A total of 884 DEGs, including 418 upregulated and downregulated genes, were identified between GBM and normal samples. The PPI network comprised a set of 3418 pairs involving 751 nodes, and AKT1 and CDK2 were the critical genes in the network. A total of seven clusters were identified, the genes in which were intensively associated with cell cycle, cholinergic synapse, and extracellular matrix (ECM)-receptor interaction. qRT-PCR analysis indicated that AKT1 and CDK2 were significantly upregulated, and NRXN3 and NPTX2 were significantly downregulated in GBM samples. The TF-miRNA-target regulatory networks were built, in which CCNB1, RFC5, microRNA524, and microRNA34b were key regulators. There were 43 genes, including NPTX2 and NRXN3, significantly related to the prognostic outcomes of GBM patients. These crucial genes might be promising options for GBM treatment.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , MicroRNAs/genética , Transcriptoma , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Células Cultivadas , Ciclina B1/genética , Ciclina B1/metabolismo , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína de Replicação C/genética , Proteína de Replicação C/metabolismo
13.
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
14.
J Clin Neurosci ; 66: 231-234, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31147230

RESUMO

Ganglioglioma (GG) is a mixed glio-neuronal tumour, comprised of a neoplastic glial component and dysplastic ganglion cells. GG is a tumour of unclear histogenesis; previous studies examining BRAF mutations and chromosome imprinting has provided evidence that both the neuronal and glial components likely arise from a common precursor. Both p.V600E mutation and KIAA1549-BRAF fusion have been described in pilocytic astrocytoma (PA) and GG, but they differ with regards to the rates of different BRAF alterations, and careful histological examination is an important component of patho-molecular correlations. More recently, cases of PA with gangliocytic differentiation (PA-GD) have been described, and these cases are thus far restricted to those with the KIAA1549-BRAF fusion. Here, we describe three cases of GGs in patients with history of previously diagnosed PAs. The cases differ with respect to the chronologic intervals between the PA and the GG diagnoses. In two of the cases, where the PA-GG diagnostic intervals are less than ten years, pathological review revealed the older specimens to have been misdiagnosed as PAs. In the third case, where the interval spanned multiple decades, the GG was found to be positive for both BRAF p.V600E immunohistochemistry (IHC) and for the KIAA1549-BRAF fusion. Molecular study for the BRAF p.V600E mutation was negative, proving the IHC result to be a false-positive. Our case demonstrates that cases of GG can harbour the KIAA1549-BRAF fusion, even with positive BRAF p.V600E IHC results, and the case highlights a diagnostic challenge that may be encountered.


Assuntos
Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Erros de Diagnóstico , Progressão da Doença , Ganglioglioma/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Adulto , Astrocitoma/genética , Neoplasias Encefálicas/genética , Feminino , Ganglioglioma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética
15.
J Clin Neurosci ; 66: 196-201, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31147232

RESUMO

Alterations in the BRAF gene have been reported to play a key role in the tumorigenesis of various tumors. Recent studies have shown the existence of BRAF alterations in ganglioglioma (GG), pilocytic astrocytoma (PA), pleomorphic xanthoastrocytomas (PXA), and epithelioid glioblastoma (eGBM). The focus of this review was the association between the clinical characteristics and BRAF status in these glial and glioneuronal tumors. The BRAF abnormalities, KIAA1549-BRAF fusion and BRAF mutation, were detected in approximately 50% of the analyzed tumors regardless of the tumor location, and there were site-specific BRAF abnormalities that became more remarkable on analysis by each tumor subtype. The median age of patients with KIAA1549-BRAF fusion was much lesser than that of those with BRAF mutations. Histological analysis indicates that the existence of KIAA1549-BRAF fusion is related to pilocytic morphology. The review of imaging features indicated that cyst formation is associated with the existence of KIAA1549-BRAF fusion in PA and GG and the lack of BRAF mutation in GG. Hemorrhage was significantly present in cases of GG with KIAA1549-BRAF fusion, but no relevance was shown in cases with BRAF mutations. No significant relevance was detected between the presence of calcification and BRAF alterations. Our clinical and genetic review of BRAF-related tumors indicated that the KIAA1549-BRAF fusion was strongly associated with PA, but not with other glial and glioneuronal tumors.


Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Ganglioglioma/genética , Glioblastoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Astrocitoma/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Ganglioglioma/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Humanos , Mutação/genética , Neuroglia/patologia
16.
BMC Cancer ; 19(1): 441, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088402

RESUMO

BACKGROUND: Glioblastoma is a disease with high heterogeneity that has long been difficult for doctors to identify and treat. ARHI is a remarkable tumor suppressor gene in human ovarian cancer and many other cancers. We found over-expression of ARHI can also inhibit cancer cell proliferation, decrease tumorigenicity, and induce autophagic cell death in human glioma and inhibition of the late stage of autophagy can further enhance the antitumor effect of ARHI through inducing apoptosis in vitro or vivo. METHODS: Using MTT assay to detect cell viability. The colony formation assay was used to measure single cell clonogenicity. Autophagy associated morphological changes were tested by transmission electron microscopy. Flow cytometry and TUNEL staining were used to measure the apoptosis rate. Autophagy inhibitor chloroquine (CQ) was used to study the effects of inhibition at late stage of autophagy on ARHI-induced autophagy and apoptosis. Protein expression were detected by Western blot, immunofluorescence and immunohistochemical analyses. LN229-derived xenografts were established to observe the effect of ARHI in vivo. RESULTS: ARHI induced autophagic death in glioma cells, and blocking late-stage autophagy markedly enhanced the antiproliferative activites of ARHI. In our research, we observed the inhibition of RAS-AKT-mTOR signaling in ARHI-glioma cells and blockade of autophagy flux at late stage by CQ enhanced the cytotoxicity of ARHI, caused accumulation of autophagic vacuoles and robust apoptosis. As a result, the inhibition of RAS augmented autophagy of glioma cells. CONCLUSION: ARHI may also be a functional tumor suppressor in glioma. And chloroquine (CQ) used as an auxiliary medicine in glioma chemotherapy can enhance the antitumor effect of ARHI, and this study provides a novel mechanistic basis and strategy for glioma therapy.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Proteínas ras/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Autofagia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Cloroquina/farmacologia , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Proteínas ras/genética , Proteínas rho de Ligação ao GTP/genética
17.
Nat Commun ; 10(1): 2045, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053733

RESUMO

Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules implicated in diverse biological processes, including therapeutic resistance. However, the mechanisms underlying lncRNA-mediated temozolomide (TMZ) resistance in glioblastoma (GBM) remain largely unknown. To illustrate the role of lncRNA in TMZ resistance, we induce TMZ-resistant GBM cells, perform a lncRNA microarray of the parental and TMZ-resistant cells, and find an unreported lncRNA in GBM, lnc-TALC (temozolomide-associated lncRNA in glioblastoma recurrence), correlated with TMZ resistance via competitively binding miR-20b-3p to facilitate c-Met expression. A phosphorylated AKT/FOXO3 axis regulated lnc-TALC expression in TMZ-resistant GBM cells. Furthermore, lnc-TALC increased MGMT expression by mediating the acetylation of H3K9, H3K27 and H3K36 in MGMT promoter regions through the c-Met/Stat3/p300 axis. In clinical patients, lnc-TALC is required for TMZ resistance and GBM recurrence. Our results reveal that lnc-TALC in GBM could serve as a therapeutic target to overcome TMZ resistance, enhancing the clinical benefits of TMZ chemotherapy.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/tratamento farmacológico , MicroRNAs/metabolismo , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , RNA Longo não Codificante/metabolismo , Temozolomida/farmacologia , Adulto , Animais , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Glioblastoma/genética , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Análise de Sobrevida , Temozolomida/uso terapêutico , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Mol Med Rep ; 19(6): 5406-5416, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059035

RESUMO

Long noncoding RNAs (lncRNAs) are a novel class of gene regulators involved in tumor biogenesis. Glioblastoma is the most common and malignant type of brain tumor. The function and prognostic significance of lncRNAs in glioblastoma remain unclear. In the present study, updated gene annotations were adopted to investigate lncRNA expression profiles in publicly available glioma microarray datasets from the Gene Expression Omnibus and the Repository for Molecular Brain Neoplasia Data. In a training set of 108 samples of glioblastoma, using univariate Cox regression analysis with a permutation P<0.005, four lncRNAs, including insulin­like growth factor binding protein 7­antisense 1 (IGFBP7­AS1), were significantly associated with patient overall survival. These four lncRNAs were integrated as an expression­based molecular signature to divide patients in the training set into high­risk and low­risk subgroups, with distinct survival rates (hazard ratio, 2.72; 95% CI, 1.71­4.31; P<0.001). The prognostic value of the lncRNA signature was confirmed in two additional datasets comprising a total of 147 samples from patients with glioblastoma. The prognostic value of this signature was independent of age and Karnofsky performance status. This signature was also able to predict different outcomes in cases of glioblastoma associated with an isocitrate dehydrogenase 1 mutation. Further bioinformatics analyses revealed that 'epithelial­mesenchymal transition' and 'p53 pathway' gene sets were enriched in glioblastoma samples with higher IGFBP7­AS1 expression. Furthermore, in vitro experiments demonstrated that knockdown of IGFBP7­AS1 inhibited the viability, migration and invasion of U87 and U251 glioma cells. In conclusion, the present study identified a lncRNA signature able to predict glioblastoma outcomes, and provided novel information regarding the role of IGFBP7­AS1 in glioma development.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , RNA Longo não Codificante/metabolismo , Transcriptoma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Linhagem Celular Tumoral , Movimento Celular , Sobrevivência Celular , Feminino , Glioblastoma/genética , Glioblastoma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Modelos de Riscos Proporcionais , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo
19.
Clin Nucl Med ; 44(7): 544-549, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31107749

RESUMO

PURPOSE: Brain metastases (BMs) in patients with differentiated thyroid cancer (DTC) are rare but associated with poor prognosis. We examined risk factors for overall survival (OS) in this population and explored the pattern of genomic alterations. METHODS: Single-institution, retrospective review of all patients with DTC from January 2000 to November 2016 identified 79 patients for analysis. Multiple prognostic factors, including age, gender, distal metastasis (DM), diagnosis time, DM sites, BM diagnosis time, BM number and size, genomic sequencing data, craniectomy, external beam radiation therapy, and kinase inhibitor therapies, were evaluated. Univariate and multivariate analyses were performed. RESULTS: Median survival after BM was 18 months. One- and 3-year survival rates were 63% and 33%, respectively. Univariate analysis identified 4 covariates correlated with prolonged survival: time between DTC diagnosis and BM for less than 3 years (P = 0.01), time from initial DM diagnosis to BM for 22 months or less (P = 0.03), 3 BM sites or fewer (P = 0.002), and craniectomy (P = 0.05). Multivariate model revealed 3 variables associated with OS: DTC diagnosis to BM time of less than 3 years (P = 0.04), craniectomy (P = 0.06), and patients with fewer than 3 BM sites (P = 0.06). The majority of patients with BM had a telomerase reverse transcriptase promoter mutation, However, mutational status was not an independent predictor of survival. CONCLUSIONS: For BM from DTC, time interval between DTC diagnosis and BM, number of BM sites, and craniectomy were independently associated with OS. Further studies are needed to define the role of genomic mutations in advanced cancer.


Assuntos
Adenocarcinoma/patologia , Neoplasias Encefálicas/secundário , Oncogenes , Neoplasias da Glândula Tireoide/patologia , Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Adulto , Idoso , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Atenção Terciária à Saúde/estatística & dados numéricos , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/genética
20.
Adv Clin Exp Med ; 28(4): 507-513, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31044567

RESUMO

BACKGROUND: Astrocytomas are diffusible infiltrative and aggressive brain tumors that are extensive and heterogeneous clusters of neoplastic growths in the central nervous system (CNS). Meningioma tumors are commonly benign but may demonstrate an invasive pattern with frequent recurrences. Human telomerase reverse transcriptase (hTERT) is an unfavorable prognostic factor for several types of cancers, and there are controversies about its role. OBJECTIVES: In the present study, we investigated the relative expression of hTERT splice variants in 2 groups of brain tumors compared to non-tumor samples. MATERIAL AND METHODS: The mRNA of 40 brain tumor samples and 4 control samples was extracted; mRNA expression of hTERT α-deletion and ß-deletion variants, as well as the wild type isoform, was quantified using quantitative reverse transcription polymerase chain reaction (RT-qPCR). RESULTS: The α-deletion variant was significantly expressed in primary benign meningeal tumors (p = 0.01). The results indicate a positive correlation between the relative expression of hTERT mRNA transcript and α-deletion and ß-deletion variants in both groups of tumors (meningiomas and astrocytomas). A strong association between the expression of the full-length splice variant and the ß-deletion variant was observed in astrocytoma tumors (p = 0.045). The most significant correlations were found between the hTERT full-length and ß-deletion variants in high-grade meningiomas (p = 0.018, correlation coefficient (CC) = 0.964) and grade II astrocytomas (p = 0.015; CC = 0.580). In addition, in low grades of both types of tumors, the hTERT full-length variant and especially the α-deletion variant were the predominant isoforms. The overexpression of hTERT and ß-deletion variants in high grades of these tumors was statistically significant. Our findings indicate that α-deletion and ß-deletion isoforms are associated with high levels of full-length hTERT mRNA in both groups of brain tumor patients. CONCLUSIONS: Changes in the splicing pattern of hTERT splice variants in brain tumors and their correlation with pathological alterations in cells could be applied as diagnostic or prognostic biomarkers, or possibly as targets for cancer therapy. However, the function and biological role of hTERT splice variants remain to be clarified.


Assuntos
Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Neoplasias Meníngeas/enzimologia , Meningioma/enzimologia , Telomerase/metabolismo , Processamento Alternativo , Neoplasias Encefálicas/patologia , Deleção de Genes , Humanos , Hidroxietilrutosídeo , Neoplasias Meníngeas/patologia , Meningioma/patologia , Recidiva Local de Neoplasia , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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