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1.
Adv Exp Med Biol ; 1202: 203-222, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32034715

RESUMO

STAT (signal transducers and activators of transcription) are latent cytoplasmic transcription factors that function as downstream effectors of cytokine and growth factor receptor signaling. The canonical JAK/STAT signaling pathway involves the activation of Janus kinases (JAK) or growth factors receptor kinases, phosphorylation of STAT proteins, their dimerization and translocation into the nucleus where STATs act as transcription factors with pleiotropic downstream effects. STAT signaling is tightly controlled with restricted kinetics due to action of its negative regulators. While STAT1 is believed to play an important role in growth arrest and apoptosis, and to act as a tumor suppressor, STAT3 and 5 are involved in promoting cell cycle progression, cellular transformation, and preventing apoptosis. Aberrant activation of STATs, in particular STAT3 and STAT5, have been found in a large number of human tumors, including gliomas and may contribute to oncogenesis. In this chapter, we have (1) summarized the mechanisms of STAT activation in normal and malignant signaling; (2) discussed evidence for the critical role of constitutively activated STAT3 and STAT5 in glioma pathobiology; (3) disclosed molecular and pharmacological strategies to interfere with STAT signaling for potential therapeutic intervention in gliomas.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioma/metabolismo , Glioma/patologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Transformação Celular Neoplásica , Humanos , Janus Quinases/metabolismo , Fosforilação
2.
J Photochem Photobiol B ; 203: 111773, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31931385

RESUMO

Glioma is the prime cause of cancer allied mortality in adolescent people and it accounts about 80% of all malignant tumours. Eugenol is a major bioactive constituent present in the essential oils with numerous pharmacological benefits including nueroprotective activity. The major drawback of eugenol is its extreme volatile property and oxygen sensitivity therefore we increased the efficacy of drug; eugenol by encapsulating with chitosan polymer. Eugenol loaded chitosan polymer (EuCs) was characterized using FTIR, XRD, SEM, HR-TEM analysis and the encapsulation, drug release efficacy was assessed at in vitro condition. The induction of autophagy and anticancer efficacy of EuCs on glioma cells was evaluated with rat C6 glioma cells using MTT assay, acridine orange staining, immunocytochemical analysis of NFκß protein expression and FLOW cytometric analysis. The anti-metastatic property of Eu-CS was assessed by immunoblotting and RT-PCR analysis of epithelial mesenchymal transition protein expression in EuCs treated rat C6 glioma cells. Our characterization analysis proves that EuCs possess essential physical and functional properties of copolymer to be utilized as a drug. Further the MTT analysis and AO staining confirms even in the presence of oncogenic inducer and autophagic inhibitors, EuCs exhibits apoptotic potency on rat C6 glioma cells. The result of immunocytochemical studies depicts the inhibition of NFκß protein expression and flow cytometry studies confirm apoptosis induction by EuCs. The inhibition of metastasis by EuCs was proven by the decrease in epithelial mesenchymal transition protein expression in Eu-Cs treated rat C6 glioma cells. Over all our results authentically confirms eugenol loaded chitosan nanopolymer persuasively induces apoptosis and inhibits metastasis in rat C6 glioma cells.


Assuntos
Antineoplásicos/química , Apoptose/efeitos dos fármacos , Quitosana/química , Eugenol/química , Metaloproteinase 9 da Matriz/metabolismo , Nanoestruturas/química , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Portadores de Fármacos/química , Eugenol/farmacologia , Glioma/metabolismo , Glioma/patologia , NF-kappa B/metabolismo , Ratos , Ativador de Plasminogênio Tipo Uroquinase/metabolismo
4.
J Colloid Interface Sci ; 559: 65-75, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610306

RESUMO

Electroactive nanofibrous scaffold is a vital tool for the study of the various biological research fields from bioelectronics to regenerative medicine, which can provide cell preferable 3D nanofiber architecture and programmed electrical signal. However, intrinsic non-biodegradability is a major problem that hinders its widespread application in the clinic. Herein, we designed, synthesized, and characterized shell/core poly (3,4-ethylenedioxythiophene) (PEDOT)/chitosan (CS) nanofibers by combining the electrospinning and recrystallization processes. Upon incorporating a trace amount of PEDOT (1.0 wt%), the resultant PEDOT/CS nanofibers exhibited low interfacial charge transfer impedance, high electrochemical stability, high electrical conductivity (up to 0.1945 S/cm), and ultrasensitive piezoelectric property (output voltage of 22.5 mV by a human hair prodding). With such unique electrical and conductive properties, PEDOT/CS nanofibers were further applied to brain neuroglioma cells (BNCs) to stimulate their adhesion, proliferation, growth, and development under an optimal external electrical stimulation (ES) and a pulse voltage of 400 mV/cm. ES-responsive PEDOT/CS nanofibers indeed promoted BNCs growth and development as indicated by a large number and density of axons. The synergetic interplay between external ES and piezoelectric voltage demonstrates new PEDOT-based nanofibers as implantable electroactive scaffolds for numerous applications in nerve tissue engineering, human health monitoring, brain mantle information extraction, and degradable microelectronic devices.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Quitosana/química , Condutividade Elétrica , Nanofibras/química , Polímeros/química , Testes de Impedância Acústica/métodos , Axônios/metabolismo , Materiais Biocompatíveis/química , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalização , Estimulação Elétrica/métodos , Glioma/metabolismo , Humanos
5.
Medicine (Baltimore) ; 98(50): e18194, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852075

RESUMO

OBJECTIVE: To date, there are several published studies on the value of IDH-1 (isocitrate dehydrogenase-1) mutation and MGMT (O6-Methylguanine-DNA methyltransferas) promoter methylated status on the diagnosis of pseudoprogression (PSP) and true tumor progression after or within chemo-radiotherapy of high grade glioma (HGG). We performed a meta-analysis about the significant value of these 2 molecular markers on the diagnosis of PsP in high- grade glioma. METHODS: We searched the eligible studies from PubMed, Medline, Embase, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI) and Wan Fang Database. The relevant studies published before October 2018 were identified. ORs (odds ratios) with 95%CIs (confidence intervals) were used to evaluate the value using fixed- or random-effect model. RESULTS: Thirteen studies about MGMT promoter methylated status and 4 studies about IDH-1 mutations were found eligible for this present meta-analysis. Significant value of MGMT promoter methylation status (OR = 4.02, 95%CI = 2.76-5.87, P < .001) and IDH-1 mutations (OR = 12.78, 95%CI = 3.86-42.35, P < .001) were observed. CONCLUSIONS: This meta-analysis provided evidences that MGMT promoter methylation status and IDH-1 mutations could distinguish PSP from true tumor progression.


Assuntos
Neoplasias Encefálicas/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , DNA de Neoplasias/genética , Glioma/genética , Isocitrato Desidrogenase/genética , Mutação , Estadiamento de Neoplasias , Proteínas Supressoras de Tumor/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/metabolismo , Metilação de DNA , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , DNA de Neoplasias/metabolismo , Progressão da Doença , Glioma/diagnóstico , Glioma/metabolismo , Humanos , Isocitrato Desidrogenase/metabolismo , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/metabolismo
6.
Anticancer Res ; 39(11): 6007-6014, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704826

RESUMO

BACKGROUND/AIM: The histone demethylase NO66 regulates gene and protein expression. Epidermal growth factor receptor (EGFR) is a key oncogenic factor for glioblastoma. This study aimed to examine the role of NO66 in glioblastoma. MATERIALS AND METHODS: The prognostic value of NO66 expression in 263 human glioma tissues and 510 glioblastoma tissues was examined by Kaplan and Meier survival analysis. Immunoblot analysis of EGFR expression, cell proliferation assays and cell cycle analysis were performed in glioblastoma cells after NO66 knockdown. RESULTS: In 263 human glioma tissues, high levels of NO66 expression correlated with advanced disease stage and poor patient prognosis. In 510 glioblastoma tissues, high levels of NO66 expression also predicted poor patient prognosis. NO66 knockdown reduced EGFR expression and cell proliferation in glioblastoma cells. CONCLUSION: High levels of NO66 in glioma and glioblastoma tissues predict poor patient prognosis, and NO66 is required for EGFR expression and glioblastoma cell proliferation.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células , Dioxigenases/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Histona Desmetilases/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Dioxigenases/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Seguimentos , Glioma/genética , Glioma/metabolismo , Histona Desmetilases/genética , Humanos , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas
7.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(5): 643-648, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31762231

RESUMO

OBJECTIVE: To study the regulation role and mechanism of protein acetylation on the expression of glioblastoma-derived neurotrophic factor (GDNF) in human glioma. METHODS: Six normal brain tissue samples, six low-grade glioma brain tissue (LG-glioma), and six high-grade glioma brain tissue (HG-glioma) were collected for study. Human glioma U251 cells were treated with histone acetylase inhibitor and histone deacetylase inhibition. The mRNA level of GDNF in glioma and normal controls was detected by Real-time PCR. H3K9 acetylation level of cAMP-response element binding protein (CREB) binding region on GDNF promoter and the ability of CREB combining to GDNF promoter were detected by ChIP-PCR. The effects of histone acetylase and deacetylase inhibitors on transcription factor binding ability and GDNF expression were detected. RESULTS: The mRNA level of GDNF in HG-glioma was significantly higher than those in normal brain tissue and LG-glioma (P < 0.01). The H3K9 acetylation level of GDNF promoter region in the glioma was increased compared to that in the normal brain tissue (P < 0.01), and the acetylation level in CREB-binding region on the GDNF promoter was higher than that in the non-CREB-binding region (P < 0.01). The binding activity of CREB and GDNF promoter in HG-glioma was higher than those in normal brain tissue and LG-glioma (P < 0.05). After treatment of U251 cells with histone acetyltransferase inhibition, the level of acetylation in CREB-binding region on GDNF promoter, the binding activity of CREB and GDNF promoter was decreased, and GDNF transcription and expression were down-regulated, while histone deacetylase inhibitors had the opposite effect (P < 0.01). CONCLUSION: Histone acetylation promotes the transcription expression of GDNF in glioma by promoting the binding of transcription factor CREB to the promoter region of GDNF gene.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Glioma/metabolismo , Histonas/química , Acetilação , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Glioma/genética , Histona Acetiltransferases , Inibidores de Histona Desacetilases/farmacologia , Humanos , Regiões Promotoras Genéticas , Transcrição Genética
8.
World Neurosurg ; 131: 346-355, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31658577

RESUMO

BACKGROUND: Erythropoietin (EPO) is a cytokine primarily involved in the regulation of erythropoiesis. In response to hypoxia-ischemia, hypoxia-inducible factor 1 induces EPO production, which, in turn, inhibits apoptosis of erythroid progenitor cells. By the same mechanism and acting through other signaling pathways, EPO exerts neuroprotective effects. Increased resistance to hypoxia and decreased apoptosis are thought to be important mechanisms for tumor progression, including malignant glioma. Because recent studies have demonstrated that EPO and its receptor (EPOR) are expressed in several tumors and can promote tumor growth, in the present study, we investigated EPO and EPOR expression in human glioma and the effect of EPO administration in a rat model of glioma implantation. METHODS: Using Western blotting and immunohistochemical analysis, we examined the expression of EPO, EPOR, platelet endothelial cell adhesion molecule, and Ki-67 in human glioma specimens and experimentally induced glioma in rats. In the experimental setting, a daily dose of recombinant human EPO (rHuEPO) or saline solution were administered for 21 days in Fischer rats subjected to 9L cell line implantation. RESULTS: In both human and animal specimens, we found an increase in EPOR expression as long as the lesion presented with an increasing malignant pattern. A significant direct correlation was found between the expression of EPOR and Ki-67 and EPOR and platelet endothelial cell adhesion molecule in low- and high-grade gliomas. The rats treated with rHuEPO presented with significantly larger tumor spread compared with the saline-treated rats. CONCLUSIONS: The results of our study have shown that the EPO/EPOR complex might play a significant role in the aggressive behavior of high-grade gliomas. The larger tumor spread in rHuEPO-treated rats suggests a feasible role for EPO in the aggressiveness and progression of malignant glioma.


Assuntos
Neoplasias Encefálicas/metabolismo , Eritropoetina/metabolismo , Glioma/metabolismo , Receptores da Eritropoetina/metabolismo , Adulto , Idoso , Animais , Western Blotting , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Eritropoetina/farmacologia , Eritropoetina/fisiologia , Feminino , Glioma/etiologia , Glioma/patologia , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Transplante de Neoplasias , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Ratos Endogâmicos F344 , Receptores da Eritropoetina/fisiologia , Proteínas Recombinantes/farmacologia , Carga Tumoral/efeitos dos fármacos
9.
Cancer Imaging ; 19(1): 68, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31639060

RESUMO

OBJECTIVE: To predict vascular endothelial growth factor (VEGF) expression in patients with diffuse gliomas using radiomic analysis. MATERIALS AND METHODS: Preoperative magnetic resonance images were retrospectively obtained from 239 patients with diffuse gliomas (World Health Organization grades II-IV). The patients were randomly assigned to a training group (n = 160) or a validation group (n = 79) at a 2:1 ratio. For each patient, a total of 431 radiomic features were extracted. The minimum redundancy maximum relevance (mRMR) algorithm was used for feature selection. A machine-learning model for predicting VEGF status was then developed using the selected features and a support vector machine classifier. The predictive performance of the model was evaluated in both groups using receiver operating characteristic curve analysis, and correlations between selected features were assessed. RESULTS: Nine radiomic features were selected to generate a VEGF-associated radiomic signature of diffuse gliomas based on the mRMR algorithm. This radiomic signature consisted of two first-order statistics or related wavelet features (Entropy and Minimum) and seven textural features or related wavelet features (including Cluster Tendency and Long Run Low Gray Level Emphasis). The predictive efficiencies measured by the area under the curve were 74.1% in the training group and 70.2% in the validation group. The overall correlations between the 9 radiomic features were low in both groups. CONCLUSIONS: Radiomic analysis facilitated efficient prediction of VEGF status in diffuse gliomas, suggesting that using tumor-derived radiomic features for predicting genomic information is feasible.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Glioma/diagnóstico por imagem , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neoplasias Encefálicas/metabolismo , Feminino , Glioma/metabolismo , Humanos , Aprendizado de Máquina , Imagem por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Distribuição Aleatória , Fator A de Crescimento do Endotélio Vascular/genética
10.
Chem Biol Interact ; 314: 108841, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31586452

RESUMO

Despite the existence of multimodal therapy concepts, glioblastoma remains a tumor type with one of the worst prognoses. In particular, the poor prognosis is due to the lack of therapeutic efficacy of chemical agents and irradiation in hypoxic tumor areas. New therapeutic strategies could improve the treatment of glioblastoma. In this study, we investigated the therapeutic efficacy of a conjugate of cisplatin (DDP), a widely used chemotherapeutic agent, and betulinic acid (BA), a natural product from plane tree bark, in glioblastoma cells under different oxygen conditions. We investigated the effects of the BA-DDP conjugate κN',N''-{3-acetyloxy-BA-28-[2-(2-aminoethyl)aminoethyl]amide} dichlorido platinum(II) (APC) and its precursor 3-acetyloxy-BA-28-[2-(2-aminoethyl)aminoethyl]amide (DE9B) on cytotoxicity, cell growth, apoptosis, migration and radiosensitivity compared to BA or DDP alone under different oxygen conditions. Based on the EC50 values, the precursor DE9B exhibited the strongest cytotoxic effects of the analyzed chemotherapeutic agents. The BA-DDP conjugate APC achieved a moderate cytotoxic effect in glioma cells. Both of the newly developed agents induced cell growth delay, apoptosis and inhibition of migration. Furthermore, additive effects could be achieved in combination with irradiation. In contrast to those of BA and DDP, the cell biological effects of APC and DE9B were not influenced by the oxygen concentration. In this study, the linking of BA and DDP did not produce a compound with additive therapeutic effects on glioblastoma cell lines in vitro. Nevertheless, the results of this study suggest that the precursor DE9B is an effective BA derivative for the treatment of glioblastoma in vitro.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cisplatino/química , Complexos de Coordenação/farmacologia , Triterpenos/química , Antineoplásicos/química , Caspase 3/metabolismo , Caspase 7/metabolismo , Hipóxia Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Glioma/metabolismo , Glioma/patologia , Humanos
11.
Nat Commun ; 10(1): 4343, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554817

RESUMO

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.


Assuntos
Neoplasias Encefálicas/genética , Metilação de DNA , Epigenômica/métodos , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Receptores Proteína Tirosina Quinases/genética , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/metabolismo , Feminino , Glioma/classificação , Glioma/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptor trkA/genética , Receptor trkA/metabolismo , Análise de Sobrevida , Sequenciamento Completo do Exoma/métodos
12.
J Biol Regul Homeost Agents ; 33(5): 1451-1463, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507151

RESUMO

Gliomas represent over 50% of tumors occurring in children. Evidence suggests that glioma stem cells (GSCs), maintained by the transforming growth factor-beta (TGF-ß1) pathway, and vascularization substantially contribute to tumor aggressiveness. The identification of important angiogenic factors such as vascular endothelial growth factor (VEGF) may represent a crucial step in the therapeutic approach against tumor growth and metastatic diffusion. The aim of this study was to identify the expression of TGF-ß1, VEGF and VEGF-receptors in brain gliomas. Specimens of 16 gliomas and 4 controls from children aged 0.2-14 years were used in the study. Immunohistochemical analysis and gene expression study from specimens was performed. Flow cytometry analysis on GSCs was performed to ascertain the expression of VEGF and VEGF-R2 in the tumor stem cell compartment. Newly diagnosed gliomas mainly showed moderate to strong VEGF immunostaining and increased expression of pro-inflammatory molecules in glioma cells. The proportion of TGF-ß1 positive endothelial cells was markedly lower in normal brain vessels compared to tumor vessels. These findings demonstrate that the glioma mass is constituted by a phenotypically immature anoxic central area with a proliferating hypoxic layer; the peripheral area is characterized by cell types with a higher degree of differentiation expressing pro-angiogenic factors. Our data have proven that GSCs play a central role in promoting glioma neovascularization. These findings are useful to understand glioma vascularization, have relevant implications in the therapeutic options and may favor new insights into stem cells biology and suggest therapeutic opportunities for the anti-vascular treatment strategy.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Células-Tronco Neoplásicas/citologia , Neovascularização Patológica , Fator de Crescimento Transformador beta1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adolescente , Encéfalo , Criança , Pré-Escolar , Células Endoteliais , Citometria de Fluxo , Imunofluorescência , Humanos , Lactente , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
Eur J Med Chem ; 183: 111694, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31561044

RESUMO

Isocitrate dehydrogenase 1 (IDH1), which catalyzes the conversion of isocitrate to α-ketoglutarate, is one of key enzymes in the tricarboxylic acid cycle (TCA). Hotspot mutation at Arg132 in IDH1 that alters the function of IDH1 by further converting the α-ketoglutarate(α-KG) to 2-hydroxyglutarate (2-HG) have been identified in a variety of cancers. Because the IDH1 mutations occur in a significant portion of gliomas and glioblastomas, it is important that IDH1 inhibitors have to be brain penetrant to treat IDH1-mutant brain tumors. Here we report the efforts to design and synthesize a novel serial of mutant IDH1 inhibitors with improved activity and the blood-brain barrier (BBB) penetration. We show that compound 5 exhibits good brain exposure and potent 2-HG inhibition in a HT1080-derived mouse xenograft model, which makes it a potential preclinical candidate to treat IDH1-mutant brain tumors.


Assuntos
Antineoplásicos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Descoberta de Drogas , Glioma/tratamento farmacológico , Isocitrato Desidrogenase/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glioma/metabolismo , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
14.
Clin Nucl Med ; 44(12): 936-942, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31524681

RESUMO

PURPOSE: As well as in many others cancers, FDG uptake is correlated with the degree of malignancy in gliomas, that is, commonly high FDG uptake in high-grade gliomas. However, in clinical practice, it is not uncommon to observe high-grade gliomas with low FDG uptake. Our aim was to explore the tumor metabolism in 2 populations of high-grade gliomas presenting high or low FDG uptake. METHODS: High-resolution magic-angle spinning nuclear magnetic resonance spectroscopy was realized on tissue samples from 7 high-grade glioma patients with high FDG uptake and 5 high-grade glioma patients with low FDG uptake. Tumor metabolomics was evaluated from 42 quantified metabolites and compared by network analysis. RESULTS: Whether originating from astrocytes or oligodendrocytes, the high-grade gliomas with low FDG avidity represent a subgroup of high-grade gliomas presenting common characteristics: low aspartate, glutamate, and creatine levels, which are probably related to the impaired electron transport chain in mitochondria; high serine/glycine metabolism and so one-carbon metabolism; low glycerophosphocholine-phosphocholine ratio in membrane metabolism, which is associated with tumor aggressiveness; and finally negative MGMT methylation status. CONCLUSIONS: It seems imperative to identify this subgroup of high-grade gliomas with low FDG avidity, which is especially aggressive. Their identification could be important for early detection for a possible personalized treatment, such as antifolate treatment.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Fluordesoxiglucose F18/metabolismo , Glioma/metabolismo , Glioma/patologia , Transporte Biológico , Neoplasias Encefálicas/diagnóstico por imagem , Feminino , Glioma/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons
15.
BMC Bioinformatics ; 20(1): 463, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31500569

RESUMO

BACKGROUND: The Human Protein Atlas (HPA) aims to map human proteins via multiple technologies including imaging, proteomics and transcriptomics. Access of the HPA data is mainly via web-based interface allowing views of individual proteins, which may not be optimal for data analysis of a gene set, or automatic retrieval of original images. RESULTS: HPAanalyze is an R package for retrieving and performing exploratory analysis of data from HPA. HPAanalyze provides functionality for importing data tables and xml files from HPA, exporting and visualizing data, as well as downloading all staining images of interest. The package is free, open source, and available via Bioconductor and GitHub. We provide examples of the use of HPAanalyze to investigate proteins altered in the deadly brain tumor glioblastoma. For example, we confirm Epidermal Growth Factor Receptor elevation and Phosphatase and Tensin Homolog loss and suggest the importance of the GTP Cyclohydrolase I/Tetrahydrobiopterin pathway. Additionally, we provide an interactive website for non-programmers to explore and visualize data without the use of R. CONCLUSIONS: HPAanalyze integrates into the R workflow with the tidyverse framework, and it can be used in combination with Bioconductor packages for easy analysis of HPA data.


Assuntos
Análise de Dados , Armazenamento e Recuperação da Informação , Proteínas de Neoplasias/metabolismo , Software , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Humanos
16.
Cancer Sci ; 110(11): 3486-3496, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31483918

RESUMO

Bone morphogenetic protein (BMP) signaling plays important roles in glioblastoma multiforme (GBM), a lethal form of brain tumor. BMP reduces GBM tumorigenicity through its differentiation- and apoptosis-inducing effects on glioma-initiating cells (GIC). However, some GIC do not respond to the tumor suppressive effects of BMP. Using a phosphoreceptor tyrosine kinase array, we found that EPHA6 (erythropoietin-producing hepatocellular carcinoma receptor A6) phosphorylation was regulated by BMP-2 signaling in some GIC. Analysis of The Cancer Genome Atlas showed that EPHA6 expression was lower in patients with GBM than in the normal brain, and that high EPHA6 expression was correlated with better prognosis. EPHA6 receptor increased the susceptibility of both sensitive and resistant GIC to BMP-2-induced apoptosis. The cooperative effect on apoptosis induction depended on the kinase activity of BMP type I receptor but was independent of EPHA6 kinase function. Overexpression of the EPHA6 receptor in GIC resulted in the formation of a protein complex of EPHA6 receptor and the BMP type I receptor ALK-2, which was associated with BMP-induced apoptosis in GIC. Intracranial injection of GIC into nude mice showed that gain-of-function of EPHA6 together with BMP-2 pretreatment slowed GBM tumor progression in the mouse brain and promoted mouse survival. In summary, EPHA6 together with BMP-2 signaling led to apoptotic cell death in GIC, and thus is a putative tumor suppressor in GBM.


Assuntos
Receptores de Ativinas Tipo I/metabolismo , Apoptose , Proteína Morfogenética Óssea 2/metabolismo , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Receptor EphA6/metabolismo , Animais , Proteína Morfogenética Óssea 2/farmacologia , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Progressão da Doença , Glioblastoma/mortalidade , Glioblastoma/patologia , Glioma/metabolismo , Glioma/patologia , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fosforilação , Prognóstico , Proteínas Supressoras de Tumor/metabolismo
17.
Eur J Med Chem ; 182: 111642, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476557

RESUMO

By exploiting the power of multicomponent chemistry, a relatively small, diverse set of primary sulfonamides was synthesized and screened against a panel of human carbonic anhydrases to reveal a low-nanomolar, albeit non-selective hCA IV lead inhibitor. Investigation of the docking poses of this compound identified a hydrophilic pocket unique to hCA IV and conveniently positioned near the carboxylate functionality of the initial lead. Various residues capable of forming hydrogen bonds as well as salt bridges were placed in this pocket via a carboxamides linkage, which led to drastic improvement of potency and selectivity towards hCA IV. This improvement of the desired inhibitory profile was rationalized by the new contacts as had been envisioned. These new tool compounds were shown to possess selective, dose-dependent cytotoxicity against human glioma T98G cell line. The latter showed a substantially increased hCA IV mRNA expression under hypoxic conditions.


Assuntos
Antineoplásicos/farmacologia , Anidrase Carbônica IV/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Descoberta de Drogas , Glioma/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Anidrase Carbônica IV/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Epiteliais/efeitos dos fármacos , Glioma/metabolismo , Glioma/patologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/metabolismo , Relação Estrutura-Atividade
18.
J Exp Clin Cancer Res ; 38(1): 394, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492191

RESUMO

BACKGROUND: FAM92A1-289(abbreviated FAM289) is recognized as one of the newly-discovered putative oncogenes. However, its role and molecular mechanisms in promoting cancer progression has not yet been elucidated. This study was performed to reveal its oncogenic functions and molecular mechanisms in human glioblastoma multiforme (GBM) cell models with knockdown or overexpression of FAM289 in vitro and in vivo. METHODS: To elucidate the molecular mechanisms underlying FAM289-mediated tumor progression, the protein-protein interaction between FAM289 and Galectin-1 was verified by co-immunoprecipitation, followed by an analysis of the expression and activity of Galectin-1-associated signaling molecules. Knockdown and overexpression of FAM289 in glioma cells were applied for investigating the effects of FAM289 on cell growth, migration and invasion. The determination of FAM289 expression was performed in specimens from various stages of human gliomas. RESULTS: FAM289-galectin-1 interaction and concomitant activation of the extracellular signal-regulated kinase (ERK) pathway participated in FAM289-mediated tumor-promoting function. Since the expression of DNA methyl transferase 1 (DNMT1) and DNA methyl transferase 3B (DNMT3B) was regulated by FAM289 in U251 and U87-MG glioma cells, Galectin-1 interaction with FAM289 may promote FAM289 protein into the cell nucleus and activate the ERK pathway, thereby upregulating DNMTs expression. Drug resistance tests indicated that FAM289-mediated TMZ resistance was through stem-like property acquisition by activating the ERK pathway. The correlation between FAM289, Galectin-1 expression and the clinical stage of gliomas was also verified in tissue samples from glioblastoma patients. CONCLUSIONS: Our results suggest that high expression of FAM289 in GBM tissues correlated with poor prognosis. FAM289 contributes to tumor progression in malignant glioma by interacting with Galectin-1 thereby promoting FAM289 protein translocation into the cell nucleus. FAM289 in the nucleus activated the ERK pathway, up regulated DNMTs expression and induced stem-like property gene expression which affects drug resistance of glioma cells to TMZ. This study provided functional evidence for FAM289 to be developed as a therapeutic target for cancer treatment.


Assuntos
Galectina 1/metabolismo , Glioma/genética , Glioma/metabolismo , Proteínas/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Técnicas de Silenciamento de Genes , Glioma/patologia , Humanos , Camundongos , NF-kappa B/metabolismo , Metástase Neoplásica , Estadiamento de Neoplasias , Ligação Proteica , Transdução de Sinais
19.
J Exp Clin Cancer Res ; 38(1): 395, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492194

RESUMO

BACKGROUND: Long non-coding RNA plays a crucial role in the occurrence and progression of glioma. We aimed to explore the function of LINC00174 in cell proliferation, apoptosis, migration, invasion and glycolysis of glioma cells, and investigate the molecular mechanism involved. METHODS: LINC00174 expression in glioma tissues and peritumoral brain edema (PTBE) tissues was examined by RT-qPCR and in situ hybridization. The CCK-8, TUNEL, wound healing, transwell, and ELISA assays were performed to identify the effects of LINC00174 knockdown on cell viability, apoptosis, migration, invasion, and glycolysis, respectively. RNA immunoprecipitation, dual-luciferase reporter, RNA pull down, and western blot assays were performed to explore the molecular mechanisms of LINC00174 in glioma cells. A nude mouse xenograft model was used to investigate the role of LINC00174 in xenograft glioma growth. RESULTS: LINC00174 was overexpressed in glioma tissues and cell lines. LINC00174 knockdown inhibited cell proliferation, migration, invasion and glycolysis of glioma cells, and LINC00174 exerted a tumorigenesis role. LINC00174 could interact with miR-152-3p/SLC2A1 axes. The miR-152-3p inhibitor or the SLC2A1 overexpression could rescue the anti-tumor effect of LINC00174 knockdown on glioma cells. Moreover, downregulation of LINC00174 also inhibited tumor volume and delayed the tumor growth in vivo. CONCLUSION: LINC00174 accelerated carcinogenesis of glioma via sponging miR-1523-3p and increasing the SLC2A1 expression, which could be considered as a molecular target for glioma diagnosis and therapy.


Assuntos
Glioma/genética , Glioma/metabolismo , Transportador de Glucose Tipo 1/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular , Biologia Computacional/métodos , Modelos Animais de Doenças , Progressão da Doença , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Glioma/patologia , Glioma/terapia , Glicólise , Humanos , Masculino , Camundongos , Interferência de RNA , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Exp Clin Cancer Res ; 38(1): 339, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31382985

RESUMO

BACKGROUND: Glioma initiating cells (GICs), also known as glioma stem cells (GSCs), play an important role in the progression and recurrence of glioblastoma multiforme (GBM) due to their potential for self-renewal, multiple differentiation and tumor initiation. In the recent years, Notch1 has been found to be overexpressed in GICs. However, the regulatory mechanism of Notch1 in the self-renewal and invasion ability of GICs remains unclear. This study aims to explore the effect of Notch pathway on self-renewal and invasion of GICs and the underlying mechanisms. METHODS: Bioinformatic analysis and immunohistochemistry (IHC) were performed to evaluate the expression of Notch1 and Hes1 in GBM samples. Immunofluorescent (IF) staining was performed to observe the distribution of Notch1 and CXCR4 in GBM and GICs. Both pharmacological intervention and RNA interference were employed to investigate the role of Notch1 in GICs self-renewal, invasion and tumor growth in vitro or in vivo. The crosstalk effect of Notch1 and CXCL12/CXCR4 system on GIC self-renewal and invasion was explored by sphere formation assay, limiting dilution assay and Transwell assay. Western blots were used to verify the activation of Notch1/CXCR4/AKT pathway in self-renewal, invasion and tumor growth of GICs. Luciferase reporter assay was used to testify the potential binding site of Notch1 signaling and CXCR4. The orthotopic GICs implantations were established to analyze the role and the mechanism of Notch1 in glioma progression in vivo. RESULTS: Notch1 signaling activity was elevated in GBM tissues. Notch1 and CXCR4 were both upregulated in GICs, compared to Notch1 positive glioma cells comprised a large proportion in the CD133+ glioma cell spheres, CXCR4 positive glioma cells which usually expressed Notch1 both and dispersed in the periphery of the sphere, only represent a small subset of CD133+ glioma cell spheres. Furthermore, downregulation of the Notch1 pathway by shRNA and MK0752 significantly inhibited the PI3K/AKT/mTOR signaling pathway via the decreased expression of CXCR4 in GICs, and weakened the self-renewal, invasion and tumor growth ability of GICs. CONCLUSIONS: These findings suggest that the cross-talk between Notch1 signaling and CXCL12/CXCR4 system could contribute to the self-renewal and invasion of GICs, and this discovery could help drive the design of more effective therapies in Notch1-targeted treatment of GBMs.


Assuntos
Quimiocina CXCL12/metabolismo , Glioma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Receptor Notch1/metabolismo , Receptores CXCR4/metabolismo , Transdução de Sinais , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Movimento Celular , Autorrenovação Celular , Modelos Animais de Doenças , Expressão Gênica , Glioma/genética , Glioma/mortalidade , Glioma/patologia , Xenoenxertos , Humanos , Imuno-Histoquímica , Imunofenotipagem , Camundongos , Modelos Biológicos , Células-Tronco Neoplásicas/patologia , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Notch1/genética , Serina-Treonina Quinases TOR/metabolismo
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