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1.
Medicine (Baltimore) ; 99(10): e19199, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32150058

RESUMEN

Neuroblastoma is the most prevalent malignancy in infants characterized by heterogeneous prognosis. It is critical to stratify the risks for patients with neuroblastoma. To stratify the risks for neuroblastoma, clinical characteristics of neuroblastoma patients were retrieved from the Therapeutically Applicable Research to Generate Effective Treatment program. All patients were randomly sampled into the development and validation sets. Cox regression was used to construct a prediction nomogram. The discrimination and calibration capacity of the nomogram was assessed. Prognostic index (PI) was calculated and tested to evaluate the performance of the nomogram. This nomogram demonstrated reasonable discrimination and calibration capacity. The nomogram derived PI exhibited acceptable accuracy in predicting the prognosis for neuroblastoma patients. The overall survival rate was significantly different between the PI discriminated high and low-risk patient subgroups. In conclusion, besides traditional staging systems, some newly defined risk factors could be involved in risk stratification for patients with neuroblastoma. Our nomogram may aid the risk stratification for neuroblastoma patients.


Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Neuroblastoma/diagnóstico por imagen , Nomogramas , Área Bajo la Curva , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Preescolar , China , Bases de Datos Factuales , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Imagen por Resonancia Magnética , Masculino , Estadificación de Neoplasias , Neuroblastoma/mortalidad , Neuroblastoma/patología , Pronóstico , Reproducibilidad de los Resultados , Riesgo , Análisis de Supervivencia
2.
Am Surg ; 86(2): 127-133, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-32167055

RESUMEN

Adrenal neuroblastoma (NB) is a relatively common malignancy in children. The Surveillance, Epidemiology, and End Results database was used to present demographic data and a survival analysis with the aim of making tumor management better. The Surveillance, Epidemiology, and End Results database was used to search pediatric patients (age ≤16 years) with NB from 2004 to 2013. The Kaplan-Meier method was used to calculate the overall survival. And, we used Cox regression analysis to determine hazard ratios for prognostic variables. Independent prognostic factors were selected into the nomogram to predict individual's three-, five-, and seven-year overall survival. The study included a total of 1870 pediatric patients with NB in our cohort. Overall, three-, five-, and seven-year survival rates for adrenal NB were 0.777, 0.701, and 0.665, respectively, whereas the rates for nonadrenal NB were 0.891, 0.859, and 0.832, respectively. The multivariate analysis identified age >1 year, no complete resection (CR)/CR, radiation, and regional/distant metastasis as independent predictors of mortality for adrenal NB. Concordance index of the nomogram was 0.665 (95% confidence interval, 0.627-0.703). Pediatric patients with adrenal NB have significantly worse survival than those with nonadrenal NB. Adrenal NB with age <1 year, treated with surgery, no radiation, and localized tumor leads to a better survival. There was no survival difference for patients to receive CR and no CR.


Asunto(s)
Neoplasias de las Glándulas Suprarrenales/mortalidad , Neuroblastoma/mortalidad , Adolescente , Neoplasias de las Glándulas Suprarrenales/patología , Neoplasias de las Glándulas Suprarrenales/cirugía , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Masculino , Neuroblastoma/patología , Neuroblastoma/cirugía , Nomogramas , Pronóstico , Análisis de Regresión , Programa de VERF/estadística & datos numéricos , Análisis de Supervivencia , Tasa de Supervivencia , Factores de Tiempo
3.
Life Sci ; 246: 117399, 2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-32032648

RESUMEN

AIMS: Glioblastomas are highly aggressive brain tumors with a very poor survival rate. EEF1A2, the proto-oncogenic isoform of the EEF1A translation factor family, has been found to be overexpressed and promoting tumorigenesis in multiple cancers. Interestingly, recent studies reported reduced expression of this protein in brain tumors, drawing our attention to find the functional role and mechanism of this protein in brain tumor progression. MAIN METHODS: Using representative cell line as models, the role of EEF1A2 in cell proliferation, migration and invasion were assessed using MTS assay, scratch wound-healing assay, transwell migration and invasion assay, respectively. Activation of key signaling pathways was assessed using western blots and real-time PCR. Finally, using immunohistochemistry we checked the protein levels of EEF1A2 in CNS tumors. KEY FINDINGS: EEF1A2 was found to increase the proliferative, migratory and invasive properties of cell lines of both glial and neuronal origin. PI3K activation directly correlated with EEF1A2 levels. Protein levels of key EMT markers viz. Twist, Snail, and Slug were increased upon ectopic EEF1A2 expression. Furthermore, EEF1A2 was found to affect the expression levels of key inflammatory cytokines, growth factors and matrix metalloproteases. IHC analysis showed that EEF1A2 is upregulated in tumor tissues compared to normal tissue. SIGNIFICANCE: EEF1A2 acts as an oncogene in both neuronal and glial cells and triggers an EMT program via PI3K pathway. However, it shows enhanced expression in neuronal cells of the brain than the glial cells, which could explain the previously reported anomaly.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Transición Epitelial-Mesenquimal , Factor 1 de Elongación Peptídica/metabolismo , Western Blotting , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Neuroblastoma/metabolismo , Neuroblastoma/patología , Factor 1 de Elongación Peptídica/fisiología , Reacción en Cadena en Tiempo Real de la Polimerasa , Transcriptoma
4.
J Photochem Photobiol B ; 203: 111748, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31918235

RESUMEN

Nanotechnology is an emerged field to develop the plant mediated metal based nanodrugs by green method. In this current study, the zinc oxide metal based nanoparticles were developed using (Clausena lansium (Lour.) Skeels) Peel aqueous extracts and zinc nitrate. The C.L extract zinc nanoparticleswere indicated by the sharp peak seen at 350 nm utilizing the Ultraviolet-Visible spectroscopy (UV-Vis). The high peaks indicate the presence of phytochemicals and its functional groups in ZnONPs were studied by the Fourier Transform Infrared Spectroscopy (FT-IR). The X-Ray Diffraction analysis (XRD) explores the pattern and structure of ZnONPs as spherical and base-centered monoclinic crystalline shapes. The C.L extract with Zn nanoparticles were spherical in nature and the size of the synthesized particles were about 28.42 nm respectively. The autophagy (Beclin-1, LC3-I, LC3-II and ATG4B) and apoptotic (Bax, Bcl-2 and Caspase-3) proteins were regulated by the treatment with ZnONPs in SH-SY5Y neuroblastoma cells. The DNA loss or damage was occurred in the ZnONPs treatment and it was performed using Comet assay. The ZnONPs treatment generates the ROS in the cells and decreased its stability and viability. Addition of NAC prevents ROS in the cultured SH-SY5Y cells and prevents the cells from the apoptosis. We concluded that the ZnONPs potentially kills the neuroblastoma cells by producing the intracellular ROS.


Asunto(s)
Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Nanopartículas del Metal/química , Óxido de Zinc/química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Beclina-1/metabolismo , Caspasa 3/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Clausena/química , Clausena/metabolismo , Daño del ADN/efectos de los fármacos , Tecnología Química Verde , Humanos , Nanopartículas del Metal/toxicidad , Neuroblastoma/metabolismo , Neuroblastoma/patología , Extractos Vegetales/química , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Especies Reactivas de Oxígeno/metabolismo
5.
Chemosphere ; 241: 125114, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31683445

RESUMEN

Di-(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer. It has neurotoxicity and exposure to it causes impairment of neurodevelopment, behavior and cognition. However, the molecular mechanisms responsible for the DEHP-induced neurotoxicity are not yet clearly defined. Tumor necrosis factor-induced protein 1 (TNFAIP1) was first discovered in umbilical vein endothelial cells and was further found to be important in the progress of Alzheimer's disease. Herein we explore the mechanism of TNFAIP1 in DEHP-induced neurotoxicity with the involvement of cyclic AMP response elements binding protein (CREB) signaling pathway in a mouse neuroblastoma cell line (N2a cells). We found that exposure to DEHP induced apoptosis and downregulated the expression of brain-derived neurotrophic factor (BDNF), synaptic proteins PSD 95 and synapsin-1 while upregulated the expression of TNFAIP1 and decreased the levels of phosphorylated Akt, CaMK Ⅳ, catalytic subunits of PKA and CREB in CREB signaling pathway. Knockdown of TNFAIP1 using TNFAIP1 small interfering RNA (siRNA) expression vector prevented DEHP from inhibiting CREB pathway, thus reduced apoptosis and restored expression of BDNF, PSD 95 and synapsin-1. Our data indicate that downregulation of TNFAIP1 prevents DEHP-induced neurotoxicity via activating CREB pathway. Therefore, TNFAIP1 is a potential target for relieving the DEHP-induced neurotoxicity and related neurological disorders.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Apoptosis/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Dietilhexil Ftalato/toxicidad , Síndromes de Neurotoxicidad/prevención & control , Plastificantes , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Animales , Línea Celular , Regulación hacia Abajo , Células Endoteliales/metabolismo , Células Endoteliales/patología , Regulación de la Expresión Génica/efectos de los fármacos , Ratones , Neuroblastoma/patología , Síndromes de Neurotoxicidad/etiología , Ácidos Ftálicos , Plastificantes/toxicidad
6.
Cancer Sci ; 111(1): 175-185, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31715070

RESUMEN

Neurogenic differentiation factor 1 (NeuroD1) is a transcription factor critical for promoting neuronal differentiation and maturation. NeuroD1 is involved in neuroblastoma and medulloblastoma; however, its molecular mechanism in promoting tumorigenesis remains unclear. Furthermore, the role of NeuroD1 in non-neural malignancies has not been widely characterized. Here, we found that NeuroD1 is highly expressed in colorectal cancer. NeuroD1-silencing induces the expression of p21, a master regulator of the cell cycle, leading to G2 -M phase arrest and suppression of colorectal cancer cell proliferation as well as colony formation potential. Moreover, NeuroD1-mediated regulation of p21 expression occurs in a p53-dependent manner. Through chromatin immunoprecipitation and point mutation analysis in the predicted NeuroD1 binding site of the p53 promoter, we found that NeuroD1 directly binds to the p53 promoter and suppresses its transcription, resulting in increased p53 expression in NeuroD1-silenced colorectal cancer cells. Finally, xenograft experiments demonstrated that NeuroD1-silencing suppresses colorectal cancer cell tumorigenesis potential by modulating p53 expression. These findings reveal NeuroD1 as a novel regulator of the p53/p21 axis, underscoring its importance in promoting non-neural malignancies. Furthermore, this study provides insight into the transcriptional regulation of p53.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Carcinogénesis/genética , Neoplasias Colorrectales/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Proteína p53 Supresora de Tumor/genética , Carcinogénesis/patología , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica/genética , Células HCT116 , Humanos , Neuroblastoma/genética , Neuroblastoma/patología , Regiones Promotoras Genéticas/genética , Factores de Transcripción/genética
7.
Gene ; 728: 144285, 2020 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-31838253

RESUMEN

Stroke has serious implications on patients and a huge impact on society. The current treatment regimens with drug for acute cerebral infarction are unsatisfactory. Here, we explore whether the two long non-coding RNA (lncRNA) candidates from preliminary research regulate apoptosis after cerebral infarction, and evaluate the underlying mechanism of action. Bioinformatics analysis of the lncRNA microarray in the preliminary research of our group was performed. Changes in the expression of candidate lncRNAs in SH-SY5Y cells were detected by quantitative polymerase chain reaction (qPCR) after treatment with seven different oxygen and glucose deprivation (OGD) methods. The changes were detected after transfection of cells with six small-interfering RNAs (siRNAs). Cell models were established by OGD after transfection with siRNAs. Cell viability was evaluated with the cell counting kit 8 (CCK8) assay, while TUNEL staining and flow cytometry analysis were performed to determine apoptosis. Changes in the expression and phosphorylation of three proteins were detected by western blotting after the knockdown of NR_120420. Changes in the expression and phosphorylation of P65 protein were detected by western blotting after this cell model was treated with PDTC. Cells were transfected with siNR_120420 and treated with and without PDTC, followed by analysis of cell viability and apoptosis. Bioinformatics analysis revealed that the differentially expressed lncRNAs after acute cerebral infarction were mainly involved in nuclear factor kappa B (NF-κB) and apoptosis. Expression of the two lncRNA candidates in SH-SY5Y cells was the maximum after incubation under the OGD condition for 8 h. The knockdown efficiency was more than 60% for four of the six siRNAs, and knockdown of NR_120420 increased the cell viability and decreased the percentage of TUNEL-positive cells and apoptotic cells. Knockdown of lnc-GCH1-2:3 resulted in none of these effects. Phosphorylation of NF-κB (P65) decreased significantly after the knockdown of NR_120420. Expression and phosphorylation of P65 was significantly reduced after it was treated with PDTC. The inhibitor of NF-κB (PDTC) could abolish the effect of NR_120420 on the regulation of apoptosis in this cell model. Both NR_120420 and lnc-GCH1-2:3 had significant changes in this cell model. Knockdown of NR_120420 inhibited the apoptosis of cells, while NR_120420 knockdown inhibited apoptosis after cerebral infarction by downregulating the phosphorylation of a subunit of NF-κB (P65). This study may provide new idea for improving drug treatment of acute cerebral infarction.


Asunto(s)
Apoptosis , Infarto Cerebral/patología , Glucosa/deficiencia , FN-kappa B/metabolismo , Neuroblastoma/patología , Oxígeno/metabolismo , ARN Largo no Codificante/genética , Enfermedad Aguda , Anciano , Estudios de Casos y Controles , Hipoxia de la Célula , Proliferación Celular , Infarto Cerebral/genética , Infarto Cerebral/metabolismo , Femenino , Humanos , Masculino , Análisis por Micromatrices , FN-kappa B/genética , Neuroblastoma/genética , Neuroblastoma/metabolismo , Fosforilación , Transducción de Señal , Células Tumorales Cultivadas
8.
Int J Cancer ; 146(4): 1031-1041, 2020 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-31304977

RESUMEN

Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80-540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system.


Asunto(s)
Modelos Animales de Enfermedad , Neuroblastoma/genética , Neuroblastoma/patología , Neoplasias Abdominales/genética , Neoplasias Abdominales/patología , Animales , Femenino , Heterogeneidad Genética , Xenoinjertos , Humanos , Masculino , Ratones , Ratones SCID , Neoplasias Torácicas/genética , Neoplasias Torácicas/patología , Células Tumorales Cultivadas
9.
Int J Cancer ; 146(2): 553-565, 2020 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-31173338

RESUMEN

Tumors are complex networks of constantly interacting elements: tumor cells, stromal cells, immune and stem cells, blood/lympathic vessels, nerve fibers and extracellular matrix components. These elements can influence their microenvironment through mechanical and physical signals to promote tumor cell growth. To get a better understanding of tumor biology, cooperation between multidisciplinary fields is needed. Diverse mathematic computations and algorithms have been designed to find prognostic targets and enhance diagnostic assessment. In this work, we use computational digital tools to study the topology of vitronectin, a glycoprotein of the extracellular matrix. Vitronectin is linked to angiogenesis and migration, two processes closely related to tumor cell spread. Here, we investigate whether the distribution of this molecule in the tumor stroma may confer mechanical properties affecting neuroblastoma aggressiveness. Combining image analysis and graph theory, we analyze different topological features that capture the organizational cues of vitronectin in histopathological images taken from human samples. We find that the Euler number and the branching of territorial vitronectin, two topological features, could allow for a more precise pretreatment risk stratification to guide treatment strategies in neuroblastoma patients. A large amount of recently synthesized VN would create migration tracks, pinpointed by both topological features, for malignant neuroblasts, so that dramatic change in the extracellular matrix would increase tumor aggressiveness and worsen patient outcomes.


Asunto(s)
Neuroblastoma/etiología , Neuroblastoma/genética , Vitronectina/genética , Algoritmos , Proliferación Celular/genética , Matriz Extracelular/genética , Matriz Extracelular/patología , Humanos , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Neuroblastoma/patología , Pronóstico , Riesgo , Células del Estroma/patología , Microambiente Tumoral/genética
10.
Cell Prolif ; 53(2): e12734, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31863533

RESUMEN

OBJECTIVE: We aimed to investigate the roles and underlying mechanisms of YAP in the proliferation of neuroblastoma cells. METHODS: The expression level of YAP was evaluated by Western blotting and immunocytochemistry. Cell viability, cell proliferation and growth were detected by CCK-8, PH3 and Ki67 immunostaining, and the real-time cell analyser system. The nuclear and cytoplasmic proteins of p27Kip1 were dissociated by the nuclear-cytosol extraction kit and were detected by Western blotting and immunocytochemistry. mRNA levels of Akt, CDK5 and CRM1 were determined by qRT-PCR. RESULTS: YAP was enriched in SH-SY5Y cells (a human neuroblastoma cell line). Knock-down of YAP in SH-SY5Y cells or SK-N-SH cell line (another human neuroblastoma cell line) significantly decreased cell viability, inhibited cell proliferation and growth. Mechanistically, knock-down of YAP increased the nuclear location of p27Kip1 , whereas serum-induced YAP activation decreased the nuclear location of p27Kip1 and was required for cell proliferation. Meanwhile, overexpression of YAP in these serum-starved SH-SY5Y cells decreased the nuclear location of p27Kip1 , promoted cell proliferation and overexpression of p27Kip1 in YAP-activated cells inhibited cell proliferation. Furthermore, knock-down of YAP reduced Akt mRNA and protein levels. Overexpression of Akt in YAP-downregulated cells decreased the nuclear location of p27Kip1 and accelerated the proliferation of SH-SY5Y cells. CONCLUSIONS: Our studies suggest that YAP promotes the proliferation of neuroblastoma cells through negatively controlling the nuclear location of p27Kip1 mediated by Akt.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proliferación Celular/fisiología , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factores de Transcripción/metabolismo , Línea Celular , Línea Celular Tumoral , Núcleo Celular/metabolismo , Supervivencia Celular/fisiología , Regulación hacia Abajo/fisiología , Humanos , Fosforilación/fisiología , ARN Mensajero/metabolismo , Transducción de Señal/fisiología
11.
Int J Biochem Cell Biol ; 119: 105680, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31866508

RESUMEN

It is usually accepted that prion proteins induce apoptosis in nerve cells. However, the mechanisms of PrPSc-neurotoxicity are not completely clear. Calcineurin is a Ca2+/calmodulin-dependent phosphatase. It activates autophagy, and may represent a link between deregulation of Ca2+ homeostasis and neuronal cell death. In this study, the effect of calcineurin activation mediated by human prion protein induced neuronal cell death via AMPK dephosphorylation and autophagy, was investigated. Synthetic peptides of PrP (PrP 106-126) increased calcineurin activity, without changing the levels of this protein phosphatase. Furthermore, these peptides reduced the levels of AMPK phosphorylation at threonine residue 172 and in autophagy activation. Calcineurin inhibitor, FK506, prevented this effect. The data showed that PrP-treated neurons had lower levels of AMPK than control neurons. This decrease in AMPK levels was matched via activation of autophagy. FK506 prevented the changes in AMPK and autophagy levels induced by PrP peptides. Taken together, the data demonstrated that prion peptides triggered an apoptotic cascade via calcineurin activation, which mediated AMPK dephosphorylation and autophagy activation. Therefore, these data suggest that therapeutic strategies targeting calcineurin inhibition might facilitate the management of neurodegenerative disorders including prion disease.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Calcineurina/metabolismo , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/patología , Neuronas/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Priones/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Inhibidores de la Calcineurina/farmacología , Línea Celular Tumoral , Humanos , Neuroblastoma/enzimología , Neuroblastoma/metabolismo , Neuronas/enzimología , Neuronas/metabolismo , Neuronas/patología , Fosforilación/efectos de los fármacos , Tacrolimus/farmacología
12.
Clin Nucl Med ; 45(1): 87-89, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31714275

RESUMEN

A 6-year-old girl with high-risk neuroblastoma underwent a I-MIBG scan to monitor the disease status. In addition to the known lesion in the right retroperitoneal region, there were additional foci of increased activity in the right upper quadrate of the abdomen, which were not typical bowel activity. SPECT/CT images located the activity in the cortex of the lower pole of the right kidney, which was partially calcified. Subsequent biopsy confirmed neuroblastoma metastasis to the right kidney, which is extremely rare.


Asunto(s)
Neoplasias Renales/diagnóstico por imagen , Neuroblastoma/diagnóstico por imagen , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único , 3-Yodobencilguanidina , Niño , Femenino , Humanos , Neoplasias Renales/secundario , Neuroblastoma/patología , Radiofármacos
14.
Nat Commun ; 10(1): 5026, 2019 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-31690716

RESUMEN

The majority of patients with neuroblastoma due to MYCN oncogene amplification and consequent N-Myc oncoprotein over-expression die of the disease. Here our analyses of RNA sequencing data identify the long noncoding RNA lncNB1 as one of the transcripts most over-expressed in MYCN-amplified, compared with MYCN-non-amplified, human neuroblastoma cells and also the most over-expressed in neuroblastoma compared with all other cancers. lncNB1 binds to the ribosomal protein RPL35 to enhance E2F1 protein synthesis, leading to DEPDC1B gene transcription. The GTPase-activating protein DEPDC1B induces ERK protein phosphorylation and N-Myc protein stabilization. Importantly, lncNB1 knockdown abolishes neuroblastoma cell clonogenic capacity in vitro and leads to neuroblastoma tumor regression in mice, while high levels of lncNB1 and RPL35 in human neuroblastoma tissues predict poor patient prognosis. This study therefore identifies lncNB1 and its binding protein RPL35 as key factors for promoting E2F1 protein synthesis, N-Myc protein stability and N-Myc-driven oncogenesis, and as therapeutic targets.


Asunto(s)
Carcinogénesis/genética , ARN Largo no Codificante/metabolismo , Proteínas Ribosómicas/metabolismo , Animales , Carcinogénesis/patología , Línea Celular Tumoral , Proliferación Celular/genética , Supervivencia Celular/genética , Factor de Transcripción E2F1/metabolismo , Femenino , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Proteína Proto-Oncogénica N-Myc/metabolismo , Neuroblastoma/genética , Neuroblastoma/patología , Pronóstico , Biosíntesis de Proteínas , Estabilidad Proteica , ARN Largo no Codificante/genética , Transcripción Genética , Regulación hacia Arriba/genética
15.
Zhonghua Er Ke Za Zhi ; 57(11): 863-869, 2019 Nov 02.
Artículo en Chino | MEDLINE | ID: mdl-31665841

RESUMEN

Objective: To analyze the clinical characteristics of newly treated high-risk group neuroblastoma (NB) patients with bone marrow metastasis and to explore the prognostic factors. Methods: The clinical features (sex, age, stage, risk group, pathological type, metastatic site, etc.) of 203 newly treated high-risk NB patients with bone marrow metastasis admitted to Hematology Oncology Center, Beijing Children's Hospital from January 2007 to December 2016 were analyzed retrospectively. There were 118 males (58.1%) and 85 females (41.9%). Kaplan-Meier method was used for survival analysis and Cox regression was used to analyze the prognostic factors. Results: The age at onset of the 203 patients was 41 months (9-147 months). The metastatic sites at diagnosis were as follows: bone in 195 cases (96.1%), distant lymph nodes in 104 cases (51.2%), skull and endomeninx in 61 cases (30.0%), orbit in 30 cases (14.8%), pleura in 16 cases (7.9%), liver in 13 cases(6.4%), canalis spinalis in 13 cases (6.4%), other sites in 11 cases (5.4%) and skin and soft tissue in 10 cases (4.9%). In all, 194 cases were enrolled for prognostic analysis. The follow-up time was 36 months (1 day-138 months) , and the 5-years event free survival (EFS) and overall survival (OS) were 36.1% and 39.7%, respectively. A total of 118 patients (60.8%) had events (first relapse or death) with the time to event occurrence was 15 months (1 day-72 months), whereas 112 patients (57.7%) died with the event occurrence to death time was 3 months (1 day-21 months). There was no significant difference in 5-years OS between radiotherapy group and non-radiotherapy group (42.3% vs. 38.3%, χ(2)=3.671, P=0.055). The 5-years OS in transplantation group was significantly better than the non-transplantation group (44.3% vs. 35.5%, χ(2)=8.878, P=0.003), and the radiotherapy combined transplantation group also had a better 5-years OS rate than the non-radiotherapy combined transplantation group (45.8% vs. 37.3%, χ(2)=5.945, P=0.015). Univariate survival analysis showed lactate dehydrogenase ≥ 1 500 U/L, the amplification of MYCN, the metastatic sites of orbit, canalis spinalis and pleura were associated with poor prognosis of newly diagnosed high-risk NB patients (χ(2)=21.064, 13.601, 3.998, 6.183, 15.307, all P<0.05). The amplification of MYCN and the metastatic sites of pleura were risk factors for prognosis of newly diagnosed high-risk NB patients by Cox regression models (HR=1.896,1.100, 95%CI: 1.113-3.231, 1.020-1.187, both P<0.05). Conclusions: The prognosis is unfavorable in high-risk group NB patients with BM metastasis. Radiotherapy combined with transplantation can further improve the prognosis of these patients. The amplification of MYCN and the metastatic sites of pleura were the poor prognostic factors for high-risk NB patients with bone marrow metastasis.


Asunto(s)
Neoplasias de la Médula Ósea/patología , Neuroblastoma/patología , Neoplasias de la Médula Ósea/mortalidad , Neoplasias de la Médula Ósea/radioterapia , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Masculino , Metástasis de la Neoplasia , Neuroblastoma/mortalidad , Neuroblastoma/radioterapia , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento
16.
BMC Cancer ; 19(1): 970, 2019 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-31638925

RESUMEN

BACKGROUND: Neuroblastoma (NB) is a paediatric tumour of the sympathetic nervous system. Half of all cases are defined high-risk with an overall survival less than 40% at 5 years from diagnosis. The lack of in vitro models able to recapitulate the intrinsic heterogeneity of primary NB tumours has hindered progress in understanding disease pathogenesis and therapy response. METHODS: Here we describe the establishment of 6 patient-derived organoids (PDOs) from cells of NB tumour biopsies capable of self-organising in a structure resembling the tissue of origin. RESULTS: PDOs recapitulate the histological architecture typical of the NB tumour. Moreover, PDOs expressed NB specific markers such as neural cell adhesion molecules, NB84 antigen, synaptophysin (SYP), chromogranin A (CHGA) and neural cell adhesion molecule NCAM (CD56). Analyses of whole genome genotyping array revealed that PDOs maintained patient-specific chromosomal aberrations such as MYCN amplification, deletion of 1p and gain of chromosome 17q. Furthermore, the PDOs showed stemness features and retained cellular heterogeneity reflecting the high heterogeneity of NB tumours. CONCLUSIONS: We were able to create a novel preclinical model for NB exhibiting self-renewal property and allowing to obtain a reservoir of NB patients' biological material useful for the study of NB molecular pathogenesis and to test drugs for personalised treatments.


Asunto(s)
Enfermedades del Sistema Nervioso Autónomo/genética , Enfermedades del Sistema Nervioso Autónomo/patología , Modelos Biológicos , Neuroblastoma/genética , Neuroblastoma/patología , Organoides/patología , Enfermedades del Sistema Nervioso Autónomo/metabolismo , Biomarcadores de Tumor/metabolismo , Biopsia , Niño , Preescolar , Cromogranina A/metabolismo , Aberraciones Cromosómicas , Amplificación de Genes/genética , Humanos , Lactante , Proteína Proto-Oncogénica N-Myc/genética , Neuroblastoma/metabolismo , Organoides/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sinaptofisina/metabolismo
17.
Dis Markers ; 2019: 6514608, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31583029

RESUMEN

Neuroblastoma is the most common seen solid neural tumor in children less than age one. As mutation in the miR-34b/c gene is observed in several types of human malignancies, there likely to be similar events that contribute to the pathogenesis of neuroblastoma. We hypothesize that polymorphism in the miR-34b/c gene might predispose to neuroblastoma. Here, we conducted this replication study by genotyping rs4938723 T>C from miR-34b/c in Hunan children (162 subjects with neuroblastoma and 270 control subjects) and examined its effect on the risk of neuroblastoma. We determined such association using logistic regression, adjusted for age and gender. Relative to those with TT genotype, subjects with C allele had reduced neuroblastoma risk (TC vs. TT: adjusted OR = 0.46, 95%CI = 0.30-0.71; additive model: adjusted OR = 0.64, 95%CI = 0.47-0.88; TC/CC vs. TT: adjusted OR = 0.49, 95%CI = 0.33-0.73). Stratified analysis revealed that rs4938723 TC/CC carriers were less likely to develop neuroblastoma for patients in the subgroups of age ≤ 18 months, age > 18 months, females, males, tumors in retroperitoneal, tumors in other sites, and clinical stages II, III, IV, and III+IV. Our findings verified miR-34b/c rs4938723 C variant allele as a protective factor for the risk of neuroblastoma. Further investigation of how miR-34b/c rs4938723 T>C might modify neuroblastoma risk is warranted.


Asunto(s)
Neoplasias de las Glándulas Suprarrenales/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias del Mediastino/genética , MicroARNs/genética , Neuroblastoma/genética , Neoplasias Retroperitoneales/genética , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/etnología , Neoplasias de las Glándulas Suprarrenales/patología , Alelos , Grupo de Ascendencia Continental Asiática , Estudios de Casos y Controles , Preescolar , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Modelos Logísticos , Masculino , Neoplasias del Mediastino/diagnóstico , Neoplasias del Mediastino/etnología , Neoplasias del Mediastino/patología , Mutación , Neuroblastoma/diagnóstico , Neuroblastoma/etnología , Neuroblastoma/patología , Oportunidad Relativa , Neoplasias Retroperitoneales/diagnóstico , Neoplasias Retroperitoneales/etnología , Neoplasias Retroperitoneales/patología , Riesgo
18.
Zhonghua Zhong Liu Za Zhi ; 41(10): 748-752, 2019 Oct 23.
Artículo en Chino | MEDLINE | ID: mdl-31648496

RESUMEN

Objective: To investigate the effect and mechanisms of CHL1 gene overexpression on cell viability, invasiveness and apoptosis in neuroblastoma cells. Methods: The empty plasmid (pcDNA3.1 group) and CHL1 recombinant plasmid (pcDNA3.1-CHL1 group) were transfected into SK-N-SH human neuroblastoma cells, and the untransfected cells were used as blank control. Forty-eight hours after transfection, the protein expressions of CHL1, PCNA, MMP-2, Bax, STAT3 and p-STAT3 were detected by western blot. Meanwhile, cell viability, invasion and apoptosis were detected by MTT, transwell and flow cytometry assays, respectively. Results: The expression level of CHL1 protein in pcDNA3.1-CHL1 group was 0.612±0.052, which was higher than that of pcDNA3.1 group 0.122±0.014 and blank control group 0.120±0.013, with statistically significant difference (P<0.05). After 24, 48 and 72 hours of transfection, the absorbance (A) values of SK-N-SH cells in the pcDNA3.1-CHL1 group were 0.328±0.035, 0.502±0.051 and 0.688±0.064, respectively, whereas those in the pcDNA3.1 group were 0.562±0.050, 0.796±0.065 and 0.973±0.077, respectively. The differences were statistically significant (P<0.05). The invaded cells in the pcDNA3.1-CHL1 group were 104.9±3.7, which were lower than that in the pcDNA3.1 group (175.6±4.6), with statistically significant difference (P<0.05). Additionally, the apoptotic rate of pcDNA3.1-CHL1 cells was (23.46±1.22)%, which was higher than that in pcDNA3.1 group (3.45±0.20)%(P<0.05). Furthermore, the levels of PCNA, MMP-2, Bax and p-STAT3 proteins in pcDNA3.1-CHL1 group were 0.156±0.018, 0.122±0.015, 0.285±0.032 and 0.023±0.004, respectively, whereas those in pcDNA3.1 group were 0.542±0.053, 0.196±0.021, 0.073±0.009 and 0.057±0.007, respectively. There were statistically significant differences between two groups (P<0.05). Conclusion: Overexpression of CHL1 inhibits the cell viability and invasion, as well as induces apoptosis of neuroblastoma cells, which is related to the inhibition of STAT3 signaling pathway.


Asunto(s)
Apoptosis , Proliferación Celular , Supervivencia Celular , Invasividad Neoplásica , Neuroblastoma/patología , Proteínas Supresoras de Tumor/metabolismo , Moléculas de Adhesión Celular , Línea Celular Tumoral , Humanos , Transfección , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/fisiología
19.
J Korean Med Sci ; 34(39): e254, 2019 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-31602824

RESUMEN

BACKGROUND: Neurotrophin-3 (NT-3), a member of the NT family, has only been considered an ancillary compound that provides anti-apoptotic benefits by inactivating tropomyosin receptor kinase C (TrkC)-induced apoptotic signals. However, little is known about the clinical relevance of NT-3 expression itself in neuroblastoma. The purpose of this study was to assess NT-3 expression in patients with neuroblastoma and its relevance to clinicopathologic findings and treatment outcomes. METHODS: In this study, expression of NT-3 and TrkC was analyzed using immunohistochemistry in 240 patients with newly diagnosed neuroblastoma. RESULTS: The results of the study revealed that NT-3 expression was associated with older age at diagnosis, localized tumors, and more differentiated tumors but was not associated with early treatment response (degree of residual tumor volume after three cycles of chemotherapy) and progression-free survival (PFS). However, when analysis was confined to patients with MYCN amplified tumors, NT-3 expression was associated with better early treatment response with borderline significance (P = 0.092) and higher PFS (86.9% vs. 58.2%; P = 0.044). In multivariate analysis in patients with MYCN amplified tumors, NT-3 was independent prognostic factor (hazard ratio, 0.246; 95% confidence interval, 0.061-0.997; P = 0.050). In another subgroup analysis, the early treatment response was better if NT-3 was expressed in patients without TrkC expression (P = 0.053) while it was poorer in patients with TrkC expression (P = 0.023). CONCLUSION: This study suggests that NT-3 expression in neuroblastoma has its own clinical significance independent of TrkC expression, and its prognostic significance differs depending on the status of MYCN amplification and/or TrkC expression.


Asunto(s)
Proteína Proto-Oncogénica N-Myc/metabolismo , Neuroblastoma/diagnóstico , Neurotrofina 3/metabolismo , Receptor trkC/metabolismo , Adolescente , Antineoplásicos/uso terapéutico , Niño , Preescolar , Femenino , Humanos , Inmunohistoquímica , Lactante , Recién Nacido , Masculino , Proteína Proto-Oncogénica N-Myc/genética , Estadificación de Neoplasias , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/patología , Neurotrofina 3/genética , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor trkC/genética
20.
J Biosci ; 44(4)2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31502566

RESUMEN

4,5-Dihydroxyanthraquinone-2-carboxylic acid (Rhein) has been shown to have various physiological and pharmacological properties including anticancer activity and modulatory effects on bioenergetics. In this study, we explored the impact of rhein on protein profiling of undifferentiated (UC) and differentiated (DC) SH-SY5Y cells. Besides that, the cellular morphology and expression of differentiation markers were investigated to determine the effect of rhein on retinoic acidinduced neuronal cell differentiation. Using two-dimensional gel electrophoresis and matrix-assisted laser desorption/ ionization-time-of-flight mass spectrometry we evaluated the changes in the proteome of both UC and DC SH-SY5Y cells after 24 h treatment with rhein. Validation of selected differentially expressed proteins and the assessment of neuronal differentiation markers were performed by western blotting. Proteomic analysis revealed significant changes in the abundance of 15 proteins linked to specific cellular processes such as cytoskeleton structure and regulation, mitochondrial function, energy metabolism, protein synthesis and neuronal plasticity. We also observed that the addition of rhein to the cultured cells during differentiation resulted in a significantly reduced neurite outgrowth and decreased expression of neuronal markers. These results indicate that rhein may strongly interfere with the differentiation process of SH-SY5Y neuroblastoma cells and is capable of inducing marked proteomic changes in these cells.


Asunto(s)
Antraquinonas/farmacología , Diferenciación Celular/efectos de los fármacos , Neuroblastoma/tratamiento farmacológico , Proteómica , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células-Madre Neurales/efectos de los fármacos , Neuritas/efectos de los fármacos , Neuritas/patología , Neuroblastoma/genética , Neuroblastoma/patología , Proyección Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos
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