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1.
FASEB J ; 35(7): e21688, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34143516

RESUMO

The mitochondria-associated membrane (MAM) is a functional subdomain of the endoplasmic reticulum membrane that tethers to the mitochondrial outer membrane and is essential for cellular homeostasis. A defect in MAM is involved in various neurological diseases, including amyotrophic lateral sclerosis (ALS). Recently, we and others reported that MAM was disrupted in the models expressing several ALS-linked genes, including SOD1, SIGMAR1, VAPB, TARDBP, and FUS, suggesting that MAM disruption is deeply involved in the pathomechanism of ALS. However, it is still uncertain whether MAM disruption is a common pathology in ALS, mainly due to the absence of a simple, quantitative tool for monitoring the status of MAM. In this study, to examine the effects of various ALS-causative genes on MAM, we created the following two novel MAM reporters: MAMtracker-Luc and MAMtracker-Green. The MAMtrackers could detect MAM disruption caused by suppression of SIGMAR1 or the overexpression of ALS-linked mutant SOD1 in living cells. Moreover, the MAMtrackers have an advantage in their ability to monitor reversible changes in the MAM status induced by nutritional conditions. We used the MAMtrackers with an expression plasmid library of ALS-causative genes and noted that 76% (16/21) of the genes altered MAM integrity. Our results suggest that MAM disruption is a common pathological feature in ALS. Furthermore, we anticipate our MAMtrackers, which are suitable for high-throughput assays, to be valuable tools to understand MAM dynamics.


Assuntos
Esclerose Amiotrófica Lateral/patologia , Mitocôndrias/patologia , Membranas Mitocondriais/patologia , Proteínas Mitocondriais/metabolismo , Mutação , Neuroblastoma/patologia , Esclerose Amiotrófica Lateral/etiologia , Esclerose Amiotrófica Lateral/metabolismo , Animais , Humanos , Camundongos , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Neuroblastoma/genética , Neuroblastoma/metabolismo
2.
Anticancer Res ; 41(6): 2795-2804, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34083269

RESUMO

BACKGROUND/AIM: Neuroblastoma is the most common childhood extracranial solid malignancy. Although cancer cells need iron and lipids for active cell division, possible links between iron and lipid metabolism in neuroblastomas have not been studied. MATERIALS AND METHODS: We evaluated the levels and association between iron and cholesterol on in vitro neuroblastoma cancer models. RESULTS: We found that the levels of iron and cholesterol are diverse among neuroblastoma cell lines. There is a bi-directional association between iron and cholesterol in drug-resistant neuroblastoma SK-N-AS cells. In drug-resistant neuroblastoma cells, low concentration of an iron chelator did not have an impact on iron levels, but on cellular cholesterol levels. Furthermore, a cholesterol decreasing agent, simvastatin, influenced both iron and cholesterol levels in drug-resistant neuroblastoma cells. CONCLUSION: Cholesterol decreasing agents may be more effective than iron chelators for drug-resistant neuroblastoma treatment.


Assuntos
Colesterol/metabolismo , Ferro/metabolismo , Neuroblastoma/metabolismo , Anticolesterolemiantes/farmacologia , Linhagem Celular Tumoral , Humanos , Quelantes de Ferro/farmacologia , Neuroblastoma/patologia
3.
Methods Mol Biol ; 2274: 385-389, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34050487

RESUMO

Confocal microscopy is a simple, super-resolution technique, which does not produce a marked increase in resolution compared to other advanced techniques, such as super-resolution nanoscopy. Here, we present a simple protocol to acquire "slightly, but easily resolved" images by pinhole closure (<1 airy unit) in a conventional confocal scanning microscope equipped with an avalanche photodiode, a detector with high sensitivity. We use murine neuroblastoma Neuro2a cells to demonstrate the image resolution obtained via this protocol without the use of any special software to enhance image quality.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Microscopia Confocal/instrumentação , Microscopia de Fluorescência/instrumentação , Imagem Molecular/métodos , Neuroblastoma/patologia , Software , Animais , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Células Tumorais Cultivadas
4.
Cancer Sci ; 112(7): 2921-2927, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33934450

RESUMO

Mature teratomas are usually benign tumors that rarely undergo malignant transformation. We report an advanced neuroblastoma arising in a mature teratoma of the ovary. Whole-exome sequencing identified extensive copy-neutral loss of heterozygosity (LOH) in both neuroblastoma and teratoma elements, suggesting that the neuroblastoma evolved from the teratoma. In addition, several truncating germline heterozygous variants in tumor suppressor genes, including RBL2 and FBXW12, became homozygous as a result of LOH. Collectively, we speculate that extensive LOH in teratoma cells may force heterozygous germline variants to become homozygous, which, in turn, may contribute to the development of neuroblastoma with the acquisition of additional chromosomal changes.


Assuntos
Mutação em Linhagem Germinativa , Perda de Heterozigosidade , Neoplasias Primárias Múltiplas/genética , Neuroblastoma/genética , Neoplasias Ovarianas/genética , Teratoma/genética , Adolescente , Proteínas F-Box/genética , Feminino , Homozigoto , Humanos , Neoplasias Primárias Múltiplas/tratamento farmacológico , Neoplasias Primárias Múltiplas/patologia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Proteína p130 Retinoblastoma-Like/genética , Teratoma/tratamento farmacológico , Teratoma/patologia , Sequenciamento Completo do Exoma
5.
Medicine (Baltimore) ; 100(20): e25827, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34011046

RESUMO

ABSTRACT: Neuroblastoma is an embryonal tumor of the autonomic nervous system with poor prognosis in children. In present study, we demonstrated the relationship of miRNA-34a-5p in the regulating of the Wnt/ß-catenin signaling pathway by targeting SRY-related HMG-box (SOX4)Reverse transcription-quantitative PCR was used to detect the expression levels of miRNA-34a-5p and SoX4. Western blotting was performed to assess the protein expression levels of SoX4, Wnt, MMP9, Bax, and Bcl-2. The proliferation, apoptosis, migration and invasion of neuroblastoma cells were determined using MTT, flow cytometry and Transwell assays.In this study, we sought to investigate the role of miRNA-34a-5p on neuroblastoma and the possible molecular mechanism. We had performed in-vitro and in-vivo experiments to evaluate the effects of miRNA-34a-5p on neuroblastoma cell proliferation and invasion by altering its expression level via cell transfection. On the basis of our study, miRNA-34a-5p showed decreased expression levels in neuroblastoma. Subsequently, we manipulated miRNA-34a-5p expression through cell transfection and observed abnormal expression of ß-catenin as well as the downstream targets of the Wnt/ß-catenin pathway in neuroblastoma cells. With all these evidences, we determined that miRNA-34a-5p regulated Wnt/ß-catenin pathway by targeting SOX4.In conclusion, our study demonstrates that miRNA-34a-5p can inhibit the over-activation of the Wnt/ß-catenin signaling pathway via targeting SOX4 and further regulate proliferation, invasion of neuroblastoma cells.


Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Neuroblastoma/genética , Fatores de Transcrição SOXC/genética , Via de Sinalização Wnt/genética , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Criança , Progressão da Doença , Feminino , Humanos , Masculino , Invasividade Neoplásica/genética , Neuroblastoma/patologia , Neuroblastoma/cirurgia , Fatores de Transcrição SOXC/metabolismo , beta Catenina/metabolismo
6.
Int J Nanomedicine ; 16: 3217-3240, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34007175

RESUMO

Background: GD2 is a mainstream biomarker for neuroblastoma (NB)-targeted therapy. Current anti-GD2 therapeutics exhibit several side effects since GD2 is also expressed at low levels on normal cells. Thus, current anti-GD2 therapeutics can be compromised by the coexistence of the target receptor on both cancer cells and normal cells. Propose: Aptamers are promising and invaluable molecular tools. Because of the pH difference between tumor and normal cells, in this study, we constructed a pH-sensitive aptamer-mediated drug delivery system (IGD-Targeted). Methods: In vivo Systematic Evolution of Ligands by Exponential Enrichment (SELEX) was used to generate a novel GD2 aptamer. Flow cytometry and molecular docking were applied to assess the binding specificities, affinities abilities of the aptamers. Confocal microscope, CCK8 assay, and BrdU assay were utilized to evaluate whether IGD-Targeted could only bind with GD2 at acidic environment. To evaluate whether IGD-Targeted could inhibit GD2-positive tumor and protect normal cells, in vivo living imaging, histomorphological staining, blood test, and RNA-sequencing were observed in animal model. Results: GD2 aptamer termed as DB67 could bind with GD2-positive cells with high specificity, while has minimal cross-reactivities to other negative cells. It has been validated that the i-motif in IGD-Targeted facilitates the binding specificity and affinity of the GD2 aptamer to GD2-positive NB tumor cells but does not interfere with GD2-positive normal cells at the pH of the cellular microenvironment. In addition, IGD-Targeted is capable of delivering Dox to only GD2-positive NB tumor cells and not to normal cells in vivo and in vitro, resulting in precise inhibition of tumor cells and protection of normal cells. Conclusion: This study suggests that IGD-Targeted as a promising platform for NB therapy which could show greater tumor inhibition and fewer side effects to normal cells, regardless of the existence of the same receptor on the target and nontarget cells.


Assuntos
Antineoplásicos/uso terapêutico , Aptâmeros de Nucleotídeos/química , DNA/química , Nanomedicina , Neuroblastoma/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Neuroblastoma/genética , Neuroblastoma/patologia , Técnica de Seleção de Aptâmeros , Transcriptoma/genética , Microambiente Tumoral/efeitos dos fármacos
7.
Nat Genet ; 53(5): 694-706, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33833454

RESUMO

Characterization of the progression of cellular states during human embryogenesis can provide insights into the origin of pediatric diseases. We examined the transcriptional states of neural crest- and mesoderm-derived lineages differentiating into adrenal glands, kidneys, endothelium and hematopoietic tissue between post-conception weeks 6 and 14 of human development. Our results reveal transitions connecting the intermediate mesoderm and progenitors of organ primordia, the hematopoietic system and endothelial subtypes. Unexpectedly, by using a combination of single-cell transcriptomics and lineage tracing, we found that intra-adrenal sympathoblasts at that stage are directly derived from nerve-associated Schwann cell precursors, similarly to local chromaffin cells, whereas the majority of extra-adrenal sympathoblasts arise from the migratory neural crest. In humans, this process persists during several weeks of development within the large intra-adrenal ganglia-like structures, which may also serve as reservoirs of originating cells in neuroblastoma.


Assuntos
Linhagem da Célula , Embrião de Mamíferos/metabolismo , Neuroblastoma/embriologia , Neuroblastoma/genética , Análise de Célula Única , Sistema Simpático-Suprarrenal/embriologia , Transcriptoma/genética , Animais , Células Cromafins/metabolismo , Células Cromafins/patologia , Análise por Conglomerados , Desenvolvimento Embrionário , Regulação da Expressão Gênica no Desenvolvimento , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , Camundongos , Células-Tronco Neurais/metabolismo , Neuroblastoma/patologia , Células de Schwann/metabolismo , Células de Schwann/patologia , Microambiente Tumoral
8.
Toxins (Basel) ; 13(4)2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808507

RESUMO

The suitability of a newly developed cell-based functional assay was tested for the detection of the activity of a range of neurotoxins and neuroactive pharmaceuticals which act by stimulation or inhibition of calcium-dependent neurotransmitter release. In this functional assay, a reporter enzyme is released concomitantly with the neurotransmitter from neurosecretory vesicles. The current study showed that the release of a luciferase from a differentiated human neuroblastoma-based reporter cell line (SIMA-hPOMC1-26-GLuc cells) can be stimulated by a carbachol-mediated activation of the Gq-coupled muscarinic-acetylcholine receptor and by the Ca2+-channel forming spider toxin α-latrotoxin. Carbachol-stimulated luciferase release was completely inhibited by the muscarinic acetylcholine receptor antagonist atropine and α-latrotoxin-mediated release by the Ca2+-chelator EGTA, demonstrating the specificity of luciferase-release stimulation. SIMA-hPOMC1-26-GLuc cells express mainly L- and N-type and to a lesser extent T-type VGCC on the mRNA and protein level. In accordance with the expression profile a depolarization-stimulated luciferase release by a high K+-buffer was effectively and dose-dependently inhibited by L-type VGCC inhibitors and to a lesser extent by N-type and T-type inhibitors. P/Q- and R-type inhibitors did not affect the K+-stimulated luciferase release. In summary, the newly established cell-based assay may represent a versatile tool to analyze the biological efficiency of a range of neurotoxins and neuroactive pharmaceuticals which mediate their activity by the modulation of calcium-dependent neurotransmitter release.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Genes Reporter , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Neuroblastoma/metabolismo , Neurotoxinas/farmacologia , Vesículas Secretórias/efeitos dos fármacos , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Luciferases/genética , Luciferases/metabolismo , Neuroblastoma/genética , Neuroblastoma/patologia , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Vesículas Secretórias/genética , Vesículas Secretórias/metabolismo , Venenos de Aranha/farmacologia
9.
Toxins (Basel) ; 13(4)2021 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-33920139

RESUMO

The plant kingdom has always been a treasure trove for valuable bioactive compounds, and Citrus fruits stand out among the others. Bergamottin (BRG) and 5-geranyloxy-7-methoxycoumarin (5-G-7-MOC) are two coumarins found in different Citrus species with well-acknowledged pharmacological properties. Previously, they have been claimed to be relevant in the anti-proliferative effects exerted by bergamot essential oil (BEO) in the SH-SY5Y human neuroblastoma cells. This study was designed to verify this assumption and to assess the mechanisms underlying the anti-proliferative effect of both compounds. Our results demonstrate that BRG and 5-G-7-MOC are able to reduce the proliferation of SH-SY5Y cells, inducing apoptosis and increasing cell population in sub-G0/G1 phase. Moreover, we demonstrated the pro-oxidant activity of the two coumarins that increased reactive oxygen species and impaired mitochondrial membrane potential. From a molecular point of view, BRG and 5-G-7-MOC were able to modulate apoptosis related factors at both protein and gene levels. Lastly, we evaluated the synergistic effect of their combination, finding that the highest synergy was observed at a concentration ratio similar to that occurring in the BEO, supporting our initial hypothesis. Taken together, our results deepen the knowledge regarding the effect of BRG and 5-G-7-MOC in SH-SY5Y cells, emphasizing the relevance of their cooperation in achieving this effect.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proliferação de Células/efeitos dos fármacos , Cumarínicos/farmacologia , Furocumarinas/farmacologia , Neuroblastoma/tratamento farmacológico , Óleos Vegetais/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Espécies Reativas de Oxigênio/metabolismo
10.
FASEB J ; 35(5): e21373, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33811702

RESUMO

Hyperactivation of PARP1 is known to be a major cause of necrotic cell death by depleting NAD+ /ATP pools during Ca2+ overload which is associated with many ischemic diseases. However, little is known about how PARP1 hyperactivity is regulated during calcium overload. In this study we show that ATR kinase, well known for its role in DNA damage responses, suppresses ionomycin, glutamate, or quinolinic acid-induced necrotic death of cells including SH-SY5Y neuronal cells. We found that the inhibition of necrosis requires the kinase activity of ATR. Specifically, ATR binds to and phosphorylates PARP1 at Ser179 after the ionophore treatments. This site-specific phosphorylation inactivates PARP1, inhibiting ionophore-induced necrosis. Strikingly, all of this occurs in the absence of detectable DNA damage and signaling up to 8 hours after ionophore treatment. Furthermore, little AIF was released from mitochondria/cytoplasm for nuclear import, supporting the necrotic type of cell death in the early period of the treatments. Our results reveal a novel ATR-mediated anti-necrotic mechanism in the cellular stress response to calcium influx without DNA damage signaling.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Cálcio/metabolismo , Dano ao DNA , Necrose , Neuroblastoma/patologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Apoptose , Proteínas Mutadas de Ataxia Telangiectasia/genética , Humanos , Neuroblastoma/genética , Neuroblastoma/metabolismo , Estresse Oxidativo , Fosforilação , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas
11.
Medicine (Baltimore) ; 100(17): e24399, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33907087

RESUMO

ABSTRACT: Neuroblastoma (NB) metastasized into the mandible and spinal extradural region was rarely reported. We present a case with metastatic NB to the mandible and the spinal extradural regions. The patient received chemotherapy using NB 97 regimen and was tumor free after 8 months, but 9 months after the treatment, the patient presented with lower limb paralysis and persistent pain in maxillofacial region as well as swelling in the left mandibular area. Metastasis to the mandible and the spinal extradural regions was diagnosed based on the spinal and maxillofacial magnetic resonance imaging. Radiotherapy with a density of 2 Gy per day was given via a linear accelerator. The total dose of the intraspinal occupying lesion was subject to radiotherapy with a regimen of 30 Gy (10 fractions). For the management of the maxillofacial pain, tumor in the maxillofacial region was subject to a density of 50 Gy (25 fractions). The maxillofacial pain disappeared after a density of 10 Gy and soft tissue tumefaction was eliminated after a density of 50 Gy, and the maxillofacial appearance was much better than before. Finally, the patient died from tumor progression 2 years after diagnosis for NB.


Assuntos
Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias Mandibulares/secundário , Neuroblastoma/patologia , Neuroblastoma/secundário , Neoplasias da Coluna Vertebral/secundário , Pré-Escolar , Espaço Epidural/patologia , Evolução Fatal , Feminino , Humanos , Mandíbula/patologia
12.
Int J Mol Sci ; 22(8)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921337

RESUMO

The long-underestimated role of extracellular vesicles in cancer is now reconsidered worldwide by basic and clinical scientists, who recently highlighted novel and crucial activities of these moieties. Extracellular vesicles are now considered as king transporters of specific cargoes, including molecular components of parent cells, thus mediating a wide variety of cellular activities both in normal and neoplastic tissues. Here, we discuss the multifunctional activities and underlying mechanisms of extracellular vesicles in neuroblastoma, the most frequent common extra-cranial tumor in childhood. The ability of extracellular vesicles to cross-talk with different cells in the tumor microenvironment and to modulate an anti-tumor immune response, tumorigenesis, tumor growth, metastasis and drug resistance will be pinpointed in detail. The results obtained on the role of extracellular vesicles may represent a panel of suggestions potentially useful in practice, due to their involvement in the response to chemotherapy, and, moreover, their ability to predict resistance to standard therapies-all issues of clinical relevance.


Assuntos
Vesículas Extracelulares/genética , Neuroblastoma/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Criança , Resistencia a Medicamentos Antineoplásicos/genética , Vesículas Extracelulares/efeitos dos fármacos , Humanos , Neuroblastoma/genética , Neuroblastoma/patologia , Microambiente Tumoral/genética
13.
Int J Mol Sci ; 22(9)2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33923239

RESUMO

Hydroxyapatite has been used in medicine for many years as a biomaterial or a cover for other biomaterials in orthopedics and dentistry. This study characterized the physicochemical properties (structure, particle size and morphology, surface properties) of Li+- and Li+/Eu3+-doped nanohydroxyapatite obtained using the wet chemistry method. The potential regenerative properties against neurite damage in cultures of neuron-like cells (SH-SY5Y and PC12 after differentiation) were also studied. The effect of nanohydroxyapatite (nHAp) on the induction of repair processes in cell cultures was assessed in tests of metabolic activity, the level of free oxygen radicals and nitric oxide, and the average length of neurites. The study showed that nanohydroxyapatite influences the increase in mitochondrial activity, which is correlated with the increase in the length of neurites. It has been shown that the doping of nanohydroxyapatite with Eu3+ ions enhances the antioxidant properties of the tested nanohydroxyapatite. These basic studies indicate its potential application in the treatment of neurite damage. These studies should be continued in primary neuronal cultures and then with in vivo models.


Assuntos
Materiais Biocompatíveis/farmacologia , Durapatita/farmacologia , Nanopartículas/administração & dosagem , Regeneração Nervosa , Neuroblastoma/tratamento farmacológico , Nervos Periféricos/citologia , Animais , Humanos , Técnicas In Vitro , Nanopartículas/química , Neuroblastoma/patologia , Células PC12 , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/patologia , Ratos , Propriedades de Superfície , Células Tumorais Cultivadas
14.
Medicina (Kaunas) ; 57(3)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802932

RESUMO

The International Neuroblastoma Risk Group Staging System (INRGSS) is based on the age of patients and preoperative imaging, with attention paid to whether the primary tumor is affected by one or more of specific image-defined risk factors (IDRFs). This publication presents a 2.5-year-old boy with neuroblastoma who had an accidental ligation of the celiac trunk during tumor resection. The consequences of this complication were pancreatic and spleen ischemia and necrosis, ischemia, and perforation of the common bile duct, gallbladder, stomach, and duodenum. The aim of this publication was to highlight the great role of the radiologist in determining the indications for neuroblastoma tumor removal, especially with current vascular IDRFs, and to show how the radiologist's insightful approach can save the patient from irreversible complications.


Assuntos
Imageamento por Ressonância Magnética , Neuroblastoma , Pré-Escolar , Humanos , Masculino , Estadiamento de Neoplasias , Neuroblastoma/diagnóstico por imagem , Neuroblastoma/patologia , Neuroblastoma/cirurgia , Radiologistas , Fatores de Risco , Tomografia Computadorizada por Raios X
15.
Arch Biochem Biophys ; 703: 108853, 2021 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-33811847

RESUMO

Generation of mitochondrial reactive oxygen species (ROS), lipid peroxidation, 4-hydroxy-2-nonenal, and heat-shock protein (HSP) 47 after electron and X-ray irradiations were detected in the human neuroblastoma cell line SK-N-SH. After 10 Gy electron irradiation and 15 Gy X-ray irradiation, mitochondrial ROS production and lipid peroxidation were significantly increased. Additionally, we observed a significant increase in the levels of HSP47 after 3 and 10 Gy electron irradiation as well as 15 Gy X-ray irradiation. Furthermore, myristoylation and farnesylation were increased after 10 Gy electron and 15 Gy X-ray irradiations. We found that the level of HSP47 increased in the mitochondria after 10 Gy electron and 15 Gy X-ray irradiations. HSP47 coexisted with myristoylation and farnesylation. Furthermore, HSP47 overexpression increased mitochondrial ROS production. These results suggest that HSP47 plays an important role in mitochondria and induces mitochondrial ROS production in SK-N-SH cells.


Assuntos
Elétrons , Proteínas de Choque Térmico HSP47/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação , Neuroblastoma/patologia , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Humanos , Processamento de Proteína Pós-Traducional/efeitos da radiação , Transporte Proteico/efeitos da radiação , Raios X
16.
BMC Cancer ; 21(1): 393, 2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33838662

RESUMO

BACKGROUND: Majority of neuroblastoma patients develop metastatic disease at diagnosis and their prognosis is poor with current therapeutic approach. Major challenges are how to tackle the mechanisms responsible for tumorigenesis and metastasis. Human mesenchymal stem cells (hMSCs) may be actively involved in the constitution of cancer microenvironment. METHODS: An orthotopic neuroblastoma murine model was utilized to mimic the clinical scenario. Human neuroblastoma cell line SK-N-LP was transfected with luciferase gene, which were inoculated with/without hMSCs into the adrenal area of SCID-beige mice. The growth and metastasis of neuroblastoma was observed by using Xenogen IVIS 100 in vivo imaging and evaluating gross tumors ex vivo. The homing of hMSCs towards tumor was analyzed by tracing fluorescence signal tagged on hMSCs using CRI Maestro™ imaging system. RESULTS: hMSCs mixed with neuroblastoma cells significantly accelerated tumor growth and apparently enhanced metastasis of neuroblastoma in vivo. hMSCs could be recruited by primary tumor and also become part of the tumor microenvironment in the metastatic lesion. The metastatic potential was consistently reduced in lung and tumor when hMSCs were pre-treated with stromal cell derived factor-1 (SDF-1) blocker, AMD3100, suggesting that the SDF-1/CXCR4 axis was one of the prime movers in the metastatic process. CONCLUSIONS: hMSCs accelerated and facilitated tumor formation, growth and metastasis. Furthermore, the homing propensity of hMSCs towards both primary tumor and metastatic loci can also provide new therapeutic insights in utilizing bio-engineered hMSCs as vehicles for targeted anti-cancer therapy.


Assuntos
Comunicação Celular , Células-Tronco Mesenquimais/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Expressão Gênica , Genes Reporter , Xenoenxertos , Humanos , Transplante de Células-Tronco Mesenquimais , Camundongos , Camundongos SCID , Processos Neoplásicos , Neuroblastoma/etiologia , Receptores CXCR4/metabolismo , Carga Tumoral , Microambiente Tumoral
17.
Medicine (Baltimore) ; 100(9): e24920, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33655954

RESUMO

BACKGROUND: Previous studies have investigated the prognostic role of programmed death ligand 1 (PD-L1) expression in patients with neuroblastoma, while the results are still controversial. Therefore, we conducted a meta-analysis to clarify the relationship between the expression of PD-L1 and the prognosis of neuroblastoma. METHODS: Search electronic databases include PubMed, Cochrane, Embase, Scopus and Web of Science, and the search time is set to build the database until January 2021. Hazard ratio (HR) and 95% confidence interval (CI) were used to analyze the included results. Meta-analysis was performed using Stata 15.0 software. RESULTS: This review will be disseminated in print by peer-review. CONCLUSION: The study will provide updated evidence for the evaluation of whether the expression of PD-L1 is associated with poor prognosis in patients with neuroblastoma. ETHICS AND DISSEMINATION: The private information from individuals will not be published. This systematic review also should not damage participants' rights. Ethical approval is not available. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/FBCY6.


Assuntos
Antígeno B7-H1/genética , DNA de Neoplasias/genética , Regulação Neoplásica da Expressão Gênica , Neuroblastoma/genética , Antígeno B7-H1/biossíntese , Morte Celular/genética , Sobrevivência Celular , Humanos , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Prognóstico
18.
Nat Genet ; 53(5): 683-693, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33767450

RESUMO

Neuroblastoma is a pediatric tumor of the developing sympathetic nervous system. However, the cellular origin of neuroblastoma has yet to be defined. Here we studied the single-cell transcriptomes of neuroblastomas and normal human developing adrenal glands at various stages of embryonic and fetal development. We defined normal differentiation trajectories from Schwann cell precursors over intermediate states to neuroblasts or chromaffin cells and showed that neuroblastomas transcriptionally resemble normal fetal adrenal neuroblasts. Importantly, neuroblastomas with varying clinical phenotypes matched different temporal states along normal neuroblast differentiation trajectories, with the degree of differentiation corresponding to clinical prognosis. Our work highlights the roles of oncogenic MYCN and loss of TFAP2B in blocking differentiation and may provide the basis for designing therapeutic interventions to overcome differentiation blocks.


Assuntos
Perfilação da Expressão Gênica , Neuroblastoma/genética , Neuroblastoma/patologia , Análise de Célula Única , Glândulas Suprarrenais/embriologia , Glândulas Suprarrenais/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Estudos de Coortes , Regulação Neoplásica da Expressão Gênica , Humanos , Transcriptoma/genética , Resultado do Tratamento
19.
Clin Nucl Med ; 46(7): 540-548, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33782280

RESUMO

BACKGROUND: Recent evidence has demonstrated high expression of somatostatin receptors in neuroblastoma (NB) cells. Because of this, we endeavored to evaluate the diagnostic performance and clinical efficacy of 68Ga-DOTATATE PET/CT and peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTATATE combined with chemotherapy in pediatric NB patients. PATIENTS AND METHODS: In total, 14 pediatric patients with histopathologically confirmed NB underwent 68Ga-DOTATATE PET/CT. Among them, the patients who were refractory or relapsed after therapy with 131I-MIBG and had intensive uptake of 68Ga-DOTATATE were referred for PRRT using 177Lu-DOTATATE. Treatment response based on follow-up imaging was classified into complete response, partial response, stable disease, and progressive disease. After each cycle of PRRT, laboratory tests were performed for evaluation of hematological, renal, and hepatic toxicities. The CTCAE (Common Terminology Criteria for Adverse Events; version 4.03) was used for grading adverse event. Curie score and International Society of Pediatric Oncology Europe Neuroblastoma score were used for semiquantitative analysis of scans of patients who underwent PRRT. In addition, overall survival was calculated as the time interval between the date of the first cycle and the end of follow-up or death. RESULTS: Overall, 14 refractory NB children including 7 boys and 7 girls with a median age of 5.5 years (ranged from 4 to 9) underwent 68Ga-DOTATATE PET/CT. PET/CT was positive in 10/14 patients (71.4%), and the median number of detected lesions in positive patients was 2 (range, 1-13). Of 14 patients, 5 patients underwent PRRT, including 3 boys and 2 girls. A total of 19 PRRT cycles and 66.4 GBq 177Lu-DOTATATE were given. Among these 5 patients, 2 showed an initial complete response, which relapsed a few months later, 1 showed a partial response, and 2 showed progressive disease. According to the Kaplan-Meier test, the overall survival was estimated at 14.5 months (95% confidence interval, 8.9-20.1). In evaluation of PRRT-related toxicity according to the CTCAE, 4 patients showed grade 1, and 1 showed grade 2 leukopenia. Two patients showed grade 1, and 2 others showed grade 2 anemia. Two patients showed grade 1, and 3 patients showed grade 2 thrombocytopenia. Serum creatinine in 1 patient increased to grade 1. CONCLUSIONS: Combination of 177Lu-DOTATATE with chemotherapeutic agents might achieve worthwhile responses with low toxicity, encouraging survival in NB patients who have relapsed or are refractory to conventional therapy, including 131I-MIBG therapy. Imaging with 68Ga-DOTATATE PET/CT in such patients has a relatively high detection efficacy, demonstrating its potential use as an alternative imaging tool to conventional modalities such as 123I/131I-MIBG. However, further well-designed trials are highly warranted.


Assuntos
Radioisótopos do Iodo/uso terapêutico , Neuroblastoma/patologia , Neuroblastoma/terapia , Receptores de Peptídeos/metabolismo , Criança , Pré-Escolar , Terapia Combinada , Complexos de Coordenação , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuroblastoma/tratamento farmacológico , Neuroblastoma/radioterapia , Octreotida/análogos & derivados , Compostos Organometálicos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Receptores de Somatostatina/metabolismo , Recidiva , Falha de Tratamento
20.
Anticancer Res ; 41(3): 1171-1181, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33788708

RESUMO

BACKGROUND/AIM: We have previously reported the identification of the cytotoxic chemotype compound-I (CC-I) from a chemical library screening against glioblastoma. MATERIALS AND METHODS: The biological activity of CC-I on drug-resistant neuroblastomas [e.g., HFE gene variant C282Y stably transfected human neuroblastoma SH-SY5Y cells (C282Y HFE/SH-SY5Y), SK-N-AS] was characterized using cell culture models and in vivo mouse tumor models. RESULTS: CC-I had potent cytotoxicity on therapy-resistant neuroblastoma cells and limited cytotoxicity on human primary dermal fibroblast cells. In addition, CC-I showed a robust anti-tumor effect on therapy-resistant human neuroblastoma C282Y HFE/SH-SY5Y cells but not on SK-N-AS cells in a subcutaneous tumor model. CC-I induced phosphorylation of heat shock protein 27 (HSP27), protein kinase B (Akt), and c-Jun N-terminal kinase (JNK) in C282Y HFE/SH-SY5Y neuroblastoma cells. CONCLUSION: CC-I may be an effective therapeutic option for therapy-resistant neuroblastomas, especially if they express the C282Y HFE gene variant. Its anti-tumor effects are possibly through HSP27-Akt-JNK activation.


Assuntos
Antineoplásicos/farmacologia , Neuroblastoma/tratamento farmacológico , Tiobarbitúricos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Fibroblastos/efeitos dos fármacos , Proteínas de Choque Térmico HSP27/fisiologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Masculino , Camundongos , Neuroblastoma/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/fisiologia , Tiobarbitúricos/uso terapêutico
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