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1.
Molecules ; 29(11)2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38893336

RESUMO

Glioblastoma, the most aggressive and challenging brain tumor, is a key focus in neuro-oncology due to its rapid growth and poor prognosis. The C6 glioma cell line is often used as a glioblastoma model due to its close simulation of human glioma characteristics, including rapid expansion and invasiveness. Alongside, herbal medicine, particularly Artemisia spp., is gaining attention for its anticancer potential, offering mechanisms like apoptosis induction, cell cycle arrest, and the inhibition of angiogenesis. In this study, we optimized extraction conditions of polyphenols from Artemisia annua L. and Artemisia vulgaris L. herbs and investigated their anticancer effects in silico and in vitro. Molecular docking of the main phenolic compounds of A. annua and A. vulgaris and potential target proteins, including programmed cell death (apoptosis) pathway proteins proapoptotic Bax (PDB ID 6EB6), anti-apoptotic Bcl-2 (PDB ID G5M), and the necroptosis pathway protein (PDB ID 7MON), mixed lineage kinase domain-like protein (MLKL), in complex with receptor-interacting serine/threonine-protein kinase 3 (RIPK3), revealed the high probability of their interactions, highlighting the possible influence of chlorogenic acid in modulating necroptosis processes. The cell viability of rat C6 glioma cell line was assessed using a nuclear fluorescent double-staining assay with Hoechst 33342 and propidium iodide. The extracts from A. annua and A. vulgaris have demonstrated anticancer activity in the glioblastoma model, with the synergistic effects of their combined compounds surpassing the efficacy of any single compound. Our results suggest the potential of these extracts as a basis for developing more effective glioblastoma treatments, emphasizing the importance of further research into their mechanisms of action and therapeutic applications.


Assuntos
Apoptose , Artemisia annua , Glioblastoma , Simulação de Acoplamento Molecular , Extratos Vegetais , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Artemisia annua/química , Linhagem Celular Tumoral , Humanos , Apoptose/efeitos dos fármacos , Artemisia/química , Ratos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Simulação por Computador , Sobrevivência Celular/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos
2.
Molecules ; 29(11)2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38893345

RESUMO

Among brain tumors, glioblastoma (GBM) is very challenging to treat as chemotherapeutic drugs can only penetrate the brain to a limited extent due to the blood-brain barrier (BBB). Nanoparticles can be an attractive solution for the treatment of GBM as they can transport drugs across the BBB into the tumor. In this study, normal and GBM organoids comprising six brain cell types were developed and applied to study the uptake, BBB penetration, distribution, and efficacy of fluorescent, ultrasmall gold nanoparticles (AuTio-Dox-AF647s) conjugated with doxorubicin (Dox) and AlexaFluor-647-cadaverine (AF647) by confocal laser scanning microscopy (CLSM), using a mixture of dissolved doxorubicin and fluorescent AF647 molecules as a control. It was shown that the nanoparticles could easily penetrate the BBB and were found in normal and GBM organoids, while the dissolved Dox and AF647 molecules alone were unable to penetrate the BBB. Flow cytometry showed a reduction in glioblastoma cells after treatment with AuTio-Dox nanoparticles, as well as a higher uptake of these nanoparticles by GBM cells in the GBM model compared to astrocytes in the normal cell organoids. In summary, our results show that ultrasmall gold nanoparticles can serve as suitable carriers for the delivery of drugs into organoids to study BBB function.


Assuntos
Barreira Hematoencefálica , Doxorrubicina , Glioblastoma , Ouro , Nanopartículas Metálicas , Organoides , Doxorrubicina/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patologia , Nanopartículas Metálicas/química , Ouro/química , Humanos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Organoides/efeitos dos fármacos , Organoides/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral
3.
Sci Rep ; 14(1): 13958, 2024 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-38886495

RESUMO

Temporal muscle thickness measured on 3D MRI has recently been linked to prognosis in glioblastoma patients and may serve as an independent prognostic indicator. This single-center study looked at temporal muscle thickness and prognosis in patients with primary glioblastoma. Overall survival was the major study outcome. For a retrospective analysis from 2010 to 2020, clinical data from 102 patients with glioblastoma at the Department of Oncology Radiotherapy of the First Affiliated Hospital of Dalian Medical University were gathered. Fifty-five cases from 2016 to 2020 contained glioblastoma molecular typing data, of which 45 were IDH wild-type glioblastomas and were analysed separately. TMT was measured on enhanced T1-weighted magnetic resonance images in patients with newly diagnosed glioblastoma.Overall patient survival (OS) was calculated by the Kaplan-Meier method and survival curves were plotted using the log-rank-sum test to determine differences between groups, and multifactorial analyses were performed using a Cox proportional-risk model.The median TMT for 102 patients was 6.775 mm (range: 4.95-10.45 mm). Patients were grouped according to median TMT, and the median overall survival (23.0 months) was significantly longer in the TMT > median group than in the TMT median group (P 0.001; Log-rank test). Analysing 45 patients with IDH wild type alone, the median overall survival (12 months) of patients in the TMT > median group was significantly longer than that of patients in the TMT ≤ median group (8 months) (P < 0.001; Log-rank test).TMT can serve as an independent prognostic factor for glioblastoma.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Imageamento por Ressonância Magnética , Músculo Temporal , Humanos , Glioblastoma/patologia , Glioblastoma/diagnóstico por imagem , Glioblastoma/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Prognóstico , Músculo Temporal/patologia , Músculo Temporal/diagnóstico por imagem , Adulto , Idoso , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/mortalidade , Estudos Retrospectivos , Imageamento por Ressonância Magnética/métodos , Estimativa de Kaplan-Meier , Isocitrato Desidrogenase/genética , Adulto Jovem
4.
Cell Commun Signal ; 22(1): 333, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890642

RESUMO

Glioblastoma (GBM) is the most common malignant brain tumor and has a dismal prognosis even under the current first-line treatment, with a 5-year survival rate less than 7%. Therefore, it is important to understand the mechanism of treatment resistance and develop new anti-tumor strategies. Induction of programmed cell death (PCD) has become a promising anti-tumor strategy, but its effectiveness in treating GBM remains controversial. On the one hand, PCD triggers tumor cell death and then release mediators to draw in immune cells, creating a pro-inflammatory tumor microenvironment (TME). One the other hand, mounting evidence suggests that PCD and inflammatory TME will force tumor cells to evolve under survival stress, leading to tumor recurrence. The purpose of this review is to summarize the role of PCD and inflammatory TME in the tumor evolution of GBM and promising methods to overcome tumor evolution.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Inflamação , Microambiente Tumoral , Glioblastoma/patologia , Glioblastoma/genética , Humanos , Inflamação/patologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Apoptose , Animais
5.
J Transl Med ; 22(1): 578, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890658

RESUMO

BACKGROUND: IDH1-wildtype glioblastoma multiforme (IDHwt-GBM) is a highly heterogeneous and aggressive brain tumour characterised by a dismal prognosis and significant challenges in accurately predicting patient outcomes. To address these issues and personalise treatment approaches, we aimed to develop and validate robust multiomics molecular subtypes of IDHwt-GBM. Through this, we sought to uncover the distinct molecular signatures underlying these subtypes, paving the way for improved diagnosis and targeted therapy for this challenging disease. METHODS: To identify stable molecular subtypes among 184 IDHwt-GBM patients from TCGA, we used the consensus clustering method to consolidate the results from ten advanced multiomics clustering approaches based on mRNA, lncRNA, and mutation data. We developed subtype prediction models using the PAM and machine learning algorithms based on mRNA and MRI data for enhanced clinical utility. These models were validated in five independent datasets, and an online interactive system was created. We conducted a comprehensive assessment of the clinical impact, drug treatment response, and molecular associations of the IDHwt-GBM subtypes. RESULTS: In the TCGA cohort, two molecular subtypes, class 1 and class 2, were identified through multiomics clustering of IDHwt-GBM patients. There was a significant difference in survival between Class 1 and Class 2 patients, with a hazard ratio (HR) of 1.68 [1.15-2.47]. This difference was validated in other datasets (CGGA: HR = 1.75[1.04, 2.94]; CPTAC: HR = 1.79[1.09-2.91]; GALSS: HR = 1.66[1.09-2.54]; UCSF: HR = 1.33[1.00-1.77]; UPENN HR = 1.29[1.04-1.58]). Additionally, class 2 was more sensitive to treatment with radiotherapy combined with temozolomide, and this sensitivity was validated in the GLASS cohort. Correspondingly, class 2 and class 1 exhibited significant differences in mutation patterns, enriched pathways, programmed cell death (PCD), and the tumour immune microenvironment. Class 2 had more mutation signatures associated with defective DNA mismatch repair (P = 0.0021). Enriched pathways of differentially expressed genes in class 1 and class 2 (P-adjust < 0.05) were mainly related to ferroptosis, the PD-1 checkpoint pathway, the JAK-STAT signalling pathway, and other programmed cell death and immune-related pathways. The different cell death modes and immune microenvironments were validated across multiple datasets. Finally, our developed survival prediction model, which integrates molecular subtypes, age, and sex, demonstrated clinical benefits based on the decision curve in the test set. We deployed the molecular subtyping prediction model and survival prediction model online, allowing interactive use and facilitating user convenience. CONCLUSIONS: Molecular subtypes were identified and verified through multiomics clustering in IDHwt-GBM patients. These subtypes are linked to specific mutation patterns, the immune microenvironment, prognoses, and treatment responses.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Isocitrato Desidrogenase , Imageamento por Ressonância Magnética , RNA Mensageiro , Humanos , Análise por Conglomerados , Glioblastoma/genética , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Glioblastoma/terapia , Prognóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Isocitrato Desidrogenase/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Mutação/genética , Reprodutibilidade dos Testes , Estudos de Coortes , Resultado do Tratamento , Multiômica
6.
Cells ; 13(11)2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38891029

RESUMO

Glioblastoma Multiforme (GBM) is an aggressive brain tumor with a high mortality rate. Direct reprogramming of glial cells to different cell lineages, such as induced neural stem cells (iNSCs) and induced neurons (iNeurons), provides genetic tools to manipulate a cell's fate as a potential therapy for neurological diseases. NeuroD1 (ND1) is a master transcriptional factor for neurogenesis and it promotes neuronal differentiation. In the present study, we tested the hypothesis that the expression of ND1 in GBM cells can force them to differentiate toward post-mitotic neurons and halt GBM tumor progression. In cultured human GBM cell lines, including LN229, U87, and U373 as temozolomide (TMZ)-sensitive and T98G as TMZ-resistant cells, the neuronal lineage conversion was induced by an adeno-associated virus (AAV) package carrying ND1. Twenty-one days after AAV-ND1 transduction, ND1-expressing cells displayed neuronal markers MAP2, TUJ1, and NeuN. The ND1-induced transdifferentiation was regulated by Wnt signaling and markedly enhanced under a hypoxic condition (2% O2 vs. 21% O2). ND1-expressing GBM cultures had fewer BrdU-positive proliferating cells compared to vector control cultures. Increased cell death was visualized by TUNEL staining, and reduced migrative activity was demonstrated in the wound-healing test after ND1 reprogramming in both TMZ-sensitive and -resistant GBM cells. In a striking contrast to cancer cells, converted cells expressed the anti-tumor gene p53. In an orthotopical GBM mouse model, AAV-ND1-reprogrammed U373 cells were transplanted into the fornix of the cyclosporine-immunocompromised C57BL/6 mouse brain. Compared to control GBM cell-formed tumors, cells from ND1-reprogrammed cultures formed smaller tumors and expressed neuronal markers such as TUJ1 in the brain. Thus, reprogramming using a single-factor ND1 overcame drug resistance, converting malignant cells of heterogeneous GBM cells to normal neuron-like cells in vitro and in vivo. These novel observations warrant further research using patient-derived GBM cells and patient-derived xenograft (PDX) models as a potentially effective treatment for a deadly brain cancer and likely other astrocytoma tumors.


Assuntos
Reprogramação Celular , Glioblastoma , Neurônios , Glioblastoma/patologia , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Animais , Linhagem Celular Tumoral , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Camundongos , Reprogramação Celular/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Temozolomida/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética
7.
Endocr Regul ; 58(1): 144-152, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38861539

RESUMO

Objective. Serine hydroxymethyltransferase (SHMT2) plays a multifunctional role in mitochondria (folate-dependent tRNA methylation, translation, and thymidylate synthesis). The endoplasmic reticulum stress, hypoxia, and glucose and glutamine supply are significant factors of malignant tumor growth including glioblastoma. Previous studies have shown that the knockdown of the endoplasmic reticulum to nucleus signaling 1 (ERN1) pathway of endoplasmic reticulum stress strongly suppressed glioblastoma cell proliferation and modified the sensitivity of these cells to hypoxia and glucose or glutamine deprivations. The present study aimed to investigate the regulation of the SHMT2 gene in U87MG glioblastoma cells by ERN1 knockdown, hypoxia, and glucose or glutamine deprivations with the intent to reveal the role of ERN1 signaling in sensitivity of this gene expression to hypoxia and nutrient supply. Methods. The control U87MG glioblastoma cells (transfected by an empty vector) and ERN1 knockdown cells with inhibited ERN1 endoribonuclease and protein kinase (dnERN1) or only ERN1 endoribonuclease (dnrERN1) were used. Hypoxia was introduced by dimethyloxalylglycine (500 ng/ml for 4 h). For glucose and glutamine deprivations, cells were exposed in DMEM without glucose and glutamine, respectively for 16 h. RNA was extracted from cells and reverse transcribed. The expression level of the SHMT2 gene was studied by real-time qPCR and normalized to ACTB. Results. It was found that inhibition of ERN1 endoribonuclease and protein kinase in glioblastoma cells led to a down-regulation of SHMT2 gene expression in U87MG cells. At the same time, the expression of this gene did not significantly change in cells with inhibited ERN1 endoribonuclease, but tunicamycin strongly increased its expression. Moreover, the expression of the SHMT2 gene was not affected in U87MG cells after silencing of XBP1. Hypoxia up-regulated the expression level of the SHMT2 gene in both control and ERN1 knockdown U87MG cells. The expression of this gene was significantly up-regulated in glioblastoma cells under glucose and glutamine deprivations and ERN1 knockdown significantly increased the sensitivity of the SHMT2 gene to these nutrient deprivation conditions. Conclusion. The results of the present study demonstrate that the expression of the SHMT2 gene responsible for serine metabolism and formation of folate one-carbon is controlled by ERN1 protein kinase and induced by hypoxia as well as glutamine and glucose deprivation conditions in glioblastoma cells and reflects the ERN1-mediated reprogramming of sensitivity this gene expression to nutrient deprivation.


Assuntos
Estresse do Retículo Endoplasmático , Endorribonucleases , Regulação Neoplásica da Expressão Gênica , Glioblastoma , Glicina Hidroximetiltransferase , Humanos , Glicina Hidroximetiltransferase/genética , Glicina Hidroximetiltransferase/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Estresse do Retículo Endoplasmático/fisiologia , Estresse do Retículo Endoplasmático/genética , Linhagem Celular Tumoral , Endorribonucleases/genética , Endorribonucleases/metabolismo , Glucose/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Hipóxia Celular/fisiologia , Hipóxia Celular/genética , Glutamina/metabolismo , Técnicas de Silenciamento de Genes
8.
Cancer Cell ; 42(6): 934-936, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38861929

RESUMO

In this issue of Cancer Cell, Zhong et al. explore the dual role of TREM2 in glioblastoma-associated myeloid cells, demonstrating its function in promoting inflammation at the tumor-neural interface and suppression within the tumor core, influenced by the local microenvironment. These findings open up promising prospects for advancements in neuro-oncological immunotherapy.


Assuntos
Glioblastoma , Glicoproteínas de Membrana , Células Mieloides , Microambiente Tumoral , Humanos , Microambiente Tumoral/imunologia , Células Mieloides/imunologia , Células Mieloides/patologia , Células Mieloides/metabolismo , Glicoproteínas de Membrana/metabolismo , Glioblastoma/patologia , Glioblastoma/imunologia , Glioblastoma/metabolismo , Receptores Imunológicos/metabolismo , Animais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/metabolismo , Neurônios/metabolismo , Neurônios/patologia
9.
Cell Biol Toxicol ; 40(1): 44, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38862832

RESUMO

BACKGROUND: Vasculogenic mimicry (VM) is an enigmatic physiological feature that influences blood supply within glioblastoma (GBM) tumors for their sustained growth. Previous studies identify NFATC3, FOSL1 and HNRNPA2B1 as significant mediators of VEGFR2, a key player in vasculogenesis, and their molecular relationships may be crucial for VM in GBM. AIMS: The aim of this study was to understand how NFATC3, FOSL1 and HNRNPA2B1 collectively influence VM in GBM. METHODS: We have investigated the underlying gene regulatory mechanisms for VM in GBM cell lines U251 and U373 in vitro and in vivo. In vitro cell-based assays were performed to explore the role of NFATC3, FOSL1 and HNRNPA2B1 in GBM cell proliferation, VM and migration, in the context of RNA interference (RNAi)-mediated knockdown alongside corresponding controls. Western blotting and qRT-PCR assays were used to examine VEGFR2 expression levels. CO-IP was employed to detect protein-protein interactions, ChIP was used to detect DNA-protein complexes, and RIP was used to detect RNA-protein complexes. Histochemical staining was used to detect VM tube formation in vivo. RESULTS: Focusing on NFATC3, FOSL1 and HNRNPA2B1, we found each was significantly upregulated in GBM and positively correlated with VM-like cellular behaviors in U251 and U373 cell lines. Knockdown of NFATC3, FOSL1 or HNRNPA2B1 each resulted in decreased levels of VEGFR2, a key growth factor gene that drives VM, as well as the inhibition of proliferation, cell migration and extracorporeal VM activity. Chromatin immunoprecipitation (ChIP) studies and luciferase reporter gene assays revealed that NFATC3 binds to the promoter region of VEGFR2 to enhance VEGFR2 gene expression. Notably, FOSL1 interacts with NFATC3 as a co-factor to potentiate the DNA-binding capacity of NFATC3, resulting in enhanced VM-like cellular behaviors. Also, level of NFATC3 protein in cells was enhanced through HNRNPA2B1 binding of NFATC3 mRNA. Furthermore, RNAi-mediated silencing of NFATC3, FOSL1 and HNRNPA2B1 in GBM cells reduced their capacity for tumor formation and VM-like behaviors in vivo. CONCLUSION: Taken together, our findings identify NFATC3 as an important mediator of GBM tumor growth through its molecular and epistatic interactions with HNRNPA2B1 and FOSL1 to influence VEGFR2 expression and VM-like cellular behaviors.


Assuntos
Movimento Celular , Proliferação de Células , Glioblastoma , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B , Fatores de Transcrição NFATC , Neovascularização Patológica , Proteínas Proto-Oncogênicas c-fos , Humanos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/genética , Glioblastoma/irrigação sanguínea , Linhagem Celular Tumoral , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Fatores de Transcrição NFATC/metabolismo , Fatores de Transcrição NFATC/genética , Animais , Proliferação de Células/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Movimento Celular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Regulação Neoplásica da Expressão Gênica , Camundongos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/irrigação sanguínea , Camundongos Nus
10.
J Cell Mol Med ; 28(11): e18392, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38864705

RESUMO

Deciphering the lncRNA-associated competitive endogenous RNA (ceRNA) network is essential in decoding glioblastoma multiforme (GBM) pathogenesis by regulating miRNA availability and controlling mRNA stability. This study aimed to explore novel biomarkers for GBM by constructing a lncRNA-miRNA-mRNA network. A ceRNA network in GBM was constructed using lncRNA, mRNA and miRNA expression profiles from the TCGA and GEO datasets. Seed nodes were identified by protein-protein interaction (PPI) network analysis of deregulated-mRNAs (DEmRNAs) in the ceRNA network. A lncRNA-miRNA-seed network was constructed by mapping the seed nodes into the preliminary ceRNA network. The impact of the seed nodes on the overall survival (OS) of patients was assessed by the GSCA database. Functional enrichment analysis of the deregulated-lncRNAs (DElncRNA) in the ceRNA network and genes interacting with OS-related genes in the PPI network were performed. Finally, the positive correlation between seed nodes and their associated lncRNAs and the expression level of these molecules in GBM tissue compared with normal samples was validated using the GEPIA database. Our analyzes revealed that three novel regulatory axes AL161785.1/miR-139-5p/MS4A6A, LINC02611/miR-139-5p/MS4A6A and PCED1B-AS1/miR-433-3p/MS4A6A may play essential roles in GBM pathogenesis. MS4A6A is upregulated in GBM and closely associated with shorter survival time of patients. We also identified that MS4A6A expression positively correlates with genes related to tumour-associated macrophages, which induce macrophage infiltration and immune suppression. The functional enrichment analysis demonstrated that DElncRNAs are mainly involved in neuroactive ligand-receptor interaction, calcium/MAPK signalling pathway, ribosome, GABAergic/Serotonergic/Glutamatergic synapse and immune system process. In addition, genes related to MS4A6A contribute to immune and inflammatory-related biological processes. Our findings provide novel insights to understand the ceRNA regulation in GBM and identify novel prognostic biomarkers or therapeutic targets.


Assuntos
Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Glioblastoma , MicroRNAs , RNA Longo não Codificante , RNA Mensageiro , Humanos , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/mortalidade , Glioblastoma/metabolismo , RNA Longo não Codificante/genética , Prognóstico , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Mapas de Interação de Proteínas/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/metabolismo , Perfilação da Expressão Gênica , Biologia Computacional/métodos , Bases de Dados Genéticas , RNA Endógeno Competitivo
11.
Cell Mol Life Sci ; 81(1): 255, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38856747

RESUMO

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor; GBM's inevitable recurrence suggests that glioblastoma stem cells (GSC) allow these tumors to persist. Our previous work showed that FOSL1, transactivated by the STAT3 gene, functions as a tumorigenic gene in glioma pathogenesis and acts as a diagnostic marker and potential drug target in glioma patients. Accumulating evidence shows that STAT3 and NF-κB cooperate to promote the development and progression of various cancers. The link between STAT3 and NF-κB suggests that NF-κB can also transcriptionally regulate FOSL1 and contribute to gliomagenesis. To investigate downstream molecules of FOSL1, we analyzed the transcriptome after overexpressing FOSL1 in a PDX-L14 line characterized by deficient FOSL1 expression. We then conducted immunohistochemical staining for FOSL1 and NF-κB p65 using rabbit polyclonal anti-FOSL1 and NF-κB p65 in glioma tissue microarrays (TMA) derived from 141 glioma patients and 15 healthy individuals. Next, mutants of the human FOSL1 promoter, featuring mutations in essential binding sites for NF-κB were generated using a Q5 site-directed mutagenesis kit. Subsequently, we examined luciferase activity in glioma cells and compared it to the wild-type FOSL1 promoter. Then, we explored the mutual regulation between NF-κB signaling and FOSL1 by modulating the expression of NF-κB or FOSL1. Subsequently, we assessed the activity of FOSL1 and NF-κB. To understand the role of FOSL1 in cell growth and stemness, we conducted a CCK-8 assay and cell cycle analysis, assessing apoptosis and GSC markers, ALDH1, and CD133 under varying FOSL1 expression conditions. Transcriptome analyses of downstream molecules of FOSL1 show that NF-κB signaling pathway is regulated by FOSL1. NF-κB p65 protein expression correlates to the expression of FOSL1 in glioma patients, and both are associated with glioma grades. NF-κB is a crucial transcription factor activating the FOSL1 promoter in glioma cells. Mutual regulation between NF-κB and FOSL1 contributes to glioma tumorigenesis and stemness through promoting G1/S transition and inhibiting apoptosis. Therefore, the FOSL1 molecular pathway is functionally connected to NF-κB activation, enhances stemness, and is indicative that FOSL1 may potentially be a novel GBM drug target.


Assuntos
Regulação Neoplásica da Expressão Gênica , NF-kappa B , Células-Tronco Neoplásicas , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-fos , Humanos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , NF-kappa B/metabolismo , Regiões Promotoras Genéticas/genética , Linhagem Celular Tumoral , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Glioma/patologia , Glioma/genética , Glioma/metabolismo , Animais , Glioblastoma/patologia , Glioblastoma/genética , Glioblastoma/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Transcrição RelA/genética , Proliferação de Células/genética , Camundongos , Transdução de Sinais , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética
12.
J Cancer Res Clin Oncol ; 150(6): 292, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38842611

RESUMO

BACKGROUND: Glioblastoma (GBM) is a highly aggressive and prevalent brain tumor that poses significant challenges in treatment. SRSF9, an RNA-binding protein, is essential for cellular processes and implicated in cancer progression. Yet, its function and mechanism in GBM need clarification. METHODS: Bioinformatics analysis was performed to explore differential expression of SRSF9 in GBM and its prognostic relevance to glioma patients. SRSF9 and CDK1 expression in GBM cell lines and patients' tissues were quantified by RT-qPCR, Western blot or immunofluorescence assay. The role of SRSF9 in GBM cell proliferation and migration was assessed by MTT, Transwell and colony formation assays. Additionally, transcriptional regulation of CDK1 by SRSF9 was investigated using ChIP-PCR and dual-luciferase assays. RESULTS: The elevated SRSF9 expression correlates to GBM stages and poor survival of glioma patients. Through gain-of-function and loss-of-function strategies, SRSF9 was demonstrated to promote proliferation and migration of GBM cells. Bioinformatics analysis showed that SRSF9 has an impact on cell growth pathways including cell cycle checkpoints and E2F targets. Mechanistically, SRSF9 appears to bind to the promoter of CDK1 gene and increase its transcription level, thus promoting GBM cell proliferation. CONCLUSIONS: These findings uncover the cellular function of SRSF9 in GBM and highlight its therapeutic potential for GBM.


Assuntos
Neoplasias Encefálicas , Proteína Quinase CDC2 , Movimento Celular , Proliferação de Células , Glioblastoma , Fatores de Processamento de Serina-Arginina , Humanos , Glioblastoma/patologia , Glioblastoma/genética , Glioblastoma/metabolismo , Proteína Quinase CDC2/metabolismo , Proteína Quinase CDC2/genética , Fatores de Processamento de Serina-Arginina/metabolismo , Fatores de Processamento de Serina-Arginina/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Prognóstico , Feminino , Masculino , Pessoa de Meia-Idade
13.
J Transl Med ; 22(1): 540, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844944

RESUMO

The adaptability of glioblastoma (GBM) cells, encouraged by complex interactions with the tumour microenvironment (TME), currently renders GBM an incurable cancer. Despite intensive research, with many clinical trials, GBM patients rely on standard treatments including surgery followed by radiation and chemotherapy, which have been observed to induce a more aggressive phenotype in recurrent tumours. This failure to improve treatments is undoubtedly a result of insufficient models which fail to incorporate components of the human brain TME. Research has increasingly uncovered mechanisms of tumour-TME interactions that correlate to worsened patient prognoses, including tumour-associated astrocyte mitochondrial transfer, neuronal circuit remodelling and immunosuppression. This tumour hijacked TME is highly implicated in driving therapy resistance, with further alterations within the TME and tumour resulting from therapy exposure inducing increased tumour growth and invasion. Recent developments improving organoid models, including aspects of the TME, are paving an exciting future for the research and drug development for GBM, with the hopes of improving patient survival growing closer. This review focuses on GBMs interactions with the TME and their effect on tumour pathology and treatment efficiency, with a look at challenges GBM models face in sufficiently recapitulating this complex and highly adaptive cancer.


Assuntos
Neoplasias Encefálicas , Resistencia a Medicamentos Antineoplásicos , Glioblastoma , Recidiva Local de Neoplasia , Microambiente Tumoral , Humanos , Glioblastoma/patologia , Glioblastoma/terapia , Recidiva Local de Neoplasia/patologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Animais
14.
Int J Mol Sci ; 25(11)2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38891882

RESUMO

According to the WHO 2016 classification, glioblastoma is the most prevalent primary tumor in the adult central nervous system (CNS) and is categorized as grade IV. With an average lifespan of about 15 months from diagnosis, glioblastoma has a poor prognosis and presents a significant treatment challenge. Aberrant angiogenesis, which promotes tumor neovascularization and is a prospective target for molecular target treatment, is one of its unique and aggressive characteristics. Recently, the existence of glioma stem cells (GSCs) within the tumor, which are tolerant to chemotherapy and radiation, has been linked to the highly aggressive form of glioblastoma. Anti-angiogenic medications have not significantly improved overall survival (OS), despite various preclinical investigations and clinical trials demonstrating encouraging results. This suggests the need to discover new treatment options. Glioblastoma is one of the numerous cancers for which metformin, an anti-hyperglycemic medication belonging to the Biguanides family, is used as first-line therapy for type 2 diabetes mellitus (T2DM), and it has shown both in vitro and in vivo anti-tumoral activity. Based on these findings, the medication has been repurposed, which has shown the inhibition of many oncopromoter mechanisms and, as a result, identified the molecular pathways involved. Metformin inhibits cancer cell growth by blocking the LKB1/AMPK/mTOR/S6K1 pathway, leading to selective cell death in GSCs and inhibiting the proliferation of CD133+ cells. It has minimal impact on differentiated glioblastoma cells and normal human stem cells. The systematic retrieval of information was performed on PubMed. A total of 106 articles were found in a search on metformin for glioblastoma. Out of these six articles were Meta-analyses, Randomized Controlled Trials, clinical trials, and Systematic Reviews. The rest were Literature review articles. These articles were from the years 2011 to 2024. Appropriate studies were isolated, and important information from each of them was understood and entered into a database from which the information was used in this article. The clinical trials on metformin use in the treatment of glioblastoma were searched on clinicaltrials.gov. In this article, we examine and evaluate metformin's possible anti-tumoral effects on glioblastoma, determining whether or not it may appropriately function as an anti-angiogenic substance and be safely added to the treatment and management of glioblastoma patients.


Assuntos
Inibidores da Angiogênese , Glioblastoma , Metformina , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/metabolismo , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/farmacologia , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Desenvolvimento de Medicamentos , Neovascularização Patológica/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo
15.
Int J Mol Sci ; 25(11)2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38892084

RESUMO

Enhancing immune cell functions in tumors remains a major challenge in cancer immunotherapy. Natural killer cells (NK) are major innate effector cells with broad cytotoxicity against tumors. Accordingly, NK cells are ideal candidates for cancer immunotherapy, including glioblastoma (GBM). Hypoxia is a common feature of solid tumors, and tumor cells and normal cells adapt to the tumor microenvironment by upregulating the transcription factor hypoxia-inducible factor (HIF)-1α, which can be detrimental to anti-tumor effector immune cell function, including that of NK cells. We knocked out HIF-1α in human primary NK cells using clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9). Then, cellular characterizations were conducted in normoxic and hypoxic conditions. Electroporating two HIF-1α-targeting guide RNA-Cas9 protein complexes inhibited HIF-1α expression in expanded NK cells. HIF-1α knockout human NK cells, including populations in hypoxic conditions, enhanced the growth inhibition of allogeneic GBM cells and induced apoptosis in GBM-cell-derived spheroids. RNA-sequencing revealed that the cytotoxicity of HIF-1α knockout NK cells could be related to increased perforin and TNF expression. The results demonstrated that HIF-1α knockout human NK cells, including populations, enhanced cytotoxicity in an environment mimicking the hypoxic conditions of GBM. CRISPR-Cas9-mediated HIF-1α knockout NK cells, including populations, could be a promising immunotherapeutic alternative in patients with GBM.


Assuntos
Técnicas de Inativação de Genes , Glioblastoma , Subunidade alfa do Fator 1 Induzível por Hipóxia , Células Matadoras Naturais , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/imunologia , Glioblastoma/patologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Sistemas CRISPR-Cas , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Apoptose/genética , Citotoxicidade Imunológica
16.
Int J Mol Sci ; 25(11)2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38892179

RESUMO

IMP dehydrogenase (IMPDH) inhibition has emerged as a new target therapy for glioblastoma multiforme (GBM), which remains one of the most refractory tumors to date. TCGA analyses revealed distinct expression profiles of IMPDH isoenzymes in various subtypes of GBM and low-grade glioma (LGG). To dissect the mechanism(s) underlying the anti-tumor effect of IMPDH inhibition in adult GBM, we investigated how mycophenolic acid (MPA, an IMPDH inhibitor) treatment affected key oncogenic drivers in glioblastoma cells. Our results showed that MPA decreased the expression of telomerase reverse transcriptase (TERT) in both U87 and U251 cells, and the expression of O6-methylguanine-DNA methyltransferase (MGMT) in U251 cells. In support, MPA treatment reduced the amount of telomere repeats in U87 and U251 cells. TERT downregulation by MPA was associated with a significant decrease in c-Myc (a TERT transcription activator) in U87 but not U251 cells, and a dose-dependent increase in p53 and CCCTC-binding factor (CTCF) (TERT repressors) in both U87 and U251 cells. In U251 cells, MPA displayed strong cytotoxic synergy with BCNU and moderate synergy with irinotecan, oxaliplatin, paclitaxel, or temozolomide (TMZ). In U87 cells, MPA displayed strong cytotoxic synergy with all except TMZ, acting primarily through the apoptotic pathway. Our work expands the mechanistic potential of IMPDH inhibition to TERT/telomere regulation and reveals a synthetic lethality between MPA and anti-GBM drugs.


Assuntos
Glioblastoma , IMP Desidrogenase , Telomerase , Humanos , Telomerase/metabolismo , Telomerase/antagonistas & inibidores , Telomerase/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/genética , Glioblastoma/patologia , Linhagem Celular Tumoral , IMP Desidrogenase/antagonistas & inibidores , IMP Desidrogenase/metabolismo , IMP Desidrogenase/genética , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Apoptose/efeitos dos fármacos
17.
Int J Mol Sci ; 25(11)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38892305

RESUMO

Glioblastoma is a highly aggressive neoplasm and the most common primary malignant brain tumor. Endothelial tissue plays a critical role in glioblastoma growth and progression, facilitating angiogenesis, cellular communication, and tumorigenesis. In this review, we present an up-to-date and comprehensive summary of the role of endothelial cells in glioblastomas, along with an overview of recent developments in glioblastoma therapies and tumor endothelial marker identification.


Assuntos
Neoplasias Encefálicas , Células Endoteliais , Glioblastoma , Neovascularização Patológica , Glioblastoma/patologia , Glioblastoma/metabolismo , Glioblastoma/terapia , Humanos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/metabolismo , Animais , Biomarcadores Tumorais/metabolismo
18.
Int J Mol Sci ; 25(11)2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38892392

RESUMO

The current standard oncotherapy for glioblastoma is limited by several adverse side effects, leading to a short-term patient survival rate paralleled by a worsening quality of life (QoL). Recently, Complementary and Integrative Medicine's (CIM) innovative approaches have shown positive impacts in terms of better response to treatment, side effect reduction, and QoL improvement. In particular, promising potential in cancer therapy has been found in compounds coming from phyto- and mycotherapy. The objective of this study was to demonstrate the beneficial effects of a new phyto-mycotherapy supplement, named Ganostile, in the human glioblastoma cell line U251, in combination with chemotherapeutic agents, i.e., Cisplatin and a new platinum-based prodrug. Choosing a supplement dosage that mimicked oral supplementation in humans (about 1 g/day), through in vitro assays, microscopy, and cytometric analysis, it has emerged that the cells, after 48hr continuous exposure to Ganostile in combination with the chemical compounds, showed a higher mortality and a lower proliferation rate than the samples subjected to the different treatments administered individually. In conclusion, our data support the use of Ganostile in integrative oncology protocols as a promising adjuvant able to amplify conventional and new drug effects and also reducing resistance mechanisms often observed in brain tumors.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Suplementos Nutricionais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos
19.
Int J Mol Sci ; 25(11)2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38892466

RESUMO

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with few effective treatments. EGFR alterations, including expression of the truncated variant EGFRvIII, are among the most frequent genomic changes in these tumors. EGFRvIII is known to preferentially signal through STAT5 for oncogenic activation in GBM, yet targeting EGFRvIII has yielded limited clinical success to date. In this study, we employed patient-derived xenograft (PDX) models expressing EGFRvIII to determine the key points of therapeutic vulnerability within the EGFRvIII-STAT5 signaling axis in GBM. Our findings reveal that exogenous expression of paralogs STAT5A and STAT5B augments cell proliferation and that inhibition of STAT5 phosphorylation in vivo improves overall survival in combination with temozolomide (TMZ). STAT5 phosphorylation is independent of JAK1 and JAK2 signaling, instead requiring Src family kinase (SFK) activity. Saracatinib, an SFK inhibitor, attenuates phosphorylation of STAT5 and preferentially sensitizes EGFRvIII+ GBM cells to undergo apoptotic cell death relative to wild-type EGFR. Constitutively active STAT5A or STAT5B mitigates saracatinib sensitivity in EGFRvIII+ cells. In vivo, saracatinib treatment decreased survival in mice bearing EGFR WT tumors compared to the control, yet in EGFRvIII+ tumors, treatment with saracatinib in combination with TMZ preferentially improves survival.


Assuntos
Benzodioxóis , Proliferação de Células , Receptores ErbB , Glioblastoma , Quinazolinas , Fator de Transcrição STAT5 , Temozolomida , Fator de Transcrição STAT5/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/genética , Humanos , Animais , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Benzodioxóis/farmacologia , Benzodioxóis/uso terapêutico , Camundongos , Receptores ErbB/metabolismo , Fosforilação/efeitos dos fármacos , Linhagem Celular Tumoral , Temozolomida/farmacologia , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Transdução de Sinais/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Apoptose/efeitos dos fármacos , Quinases da Família src/metabolismo , Proteínas Supressoras de Tumor
20.
Cells ; 13(11)2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38891070

RESUMO

Glioblastoma (GBM) poses a significant challenge in clinical oncology due to its aggressive nature, heterogeneity, and resistance to therapies. Cancer stem cells (CSCs) play a critical role in GBM, particularly in treatment resistance and tumor relapse, emphasizing the need to comprehend the mechanisms regulating these cells. Also, their multifaceted contributions to the tumor microenvironment (TME) underline their significance, driven by their unique properties. This study aimed to characterize glioblastoma stem cells (GSCs), specifically slow-cycling cells (SCCs), in an immunocompetent murine GBM model to explore their similarities with their human counterparts. Using the KR158 mouse model, we confirmed that SCCs isolated from this model exhibited key traits and functional properties akin to human SCCs. KR158 murine SCCs, expanded in the gliomasphere assay, demonstrated sphere forming ability, self-renewing capacity, positive tumorigenicity, enhanced stemness and resistance to chemotherapy. Together, our findings validate the KR158 murine model as a framework to investigate GSCs and SCCs in GBM pathology, and explore specifically the SCC-immune system communications, understand their role in disease progression, and evaluate the effect of therapeutic strategies targeting these specific connections.


Assuntos
Células-Tronco Neoplásicas , Esferoides Celulares , Animais , Camundongos , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/metabolismo , Esferoides Celulares/patologia , Humanos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/imunologia , Glioma/patologia , Glioma/imunologia , Linhagem Celular Tumoral , Glioblastoma/patologia , Glioblastoma/imunologia , Imunocompetência , Microambiente Tumoral , Modelos Animais de Doenças , Gradação de Tumores
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