RESUMEN
Neuroblastoma (NB) is the most commonly diagnosed extracranial solid tumor in children, accounting for 15% of all childhood cancer deaths. Although the 5-year survival rate of patients with a high-risk disease has increased in recent decades, NB remains a challenge in pediatric oncology, and the identification of novel potential therapeutic targets and agents is an urgent clinical need. The RNA-binding protein LIN28B has been identified as an oncogene in NB and is associated with a poor prognosis. Given that LIN28B acts by negatively regulating the biogenesis of the tumor suppressor let-7 miRNAs, we reasoned that selective interference with the LIN28B/let-7 miRNA interaction would increase let-7 miRNA levels, ultimately leading to reduced NB aggressiveness. Here, we selected (-)-epigallocatechin 3-gallate (EGCG) out of 4959 molecules screened as the molecule with the best inhibitory activity on LIN28B/let-7 miRNA interaction and showed that treatment with PLC/PLGA-PEG nanoparticles containing EGCG (EGCG-NPs) led to an increase in mature let-7 miRNAs and a consequent inhibition of NB cell growth. In addition, EGCG-NP pretreatment reduced the tumorigenic potential of NB cells in vivo. These experiments suggest that the LIN28B/let-7 miRNA axis is a good therapeutic target in NB and that EGCG, which can interfere with this interaction, deserves further preclinical evaluation.
Asunto(s)
Catequina , MicroARNs , Neuroblastoma , Proteínas de Unión al ARN , Catequina/análogos & derivados , Catequina/farmacología , Neuroblastoma/genética , Neuroblastoma/patología , Neuroblastoma/metabolismo , Neuroblastoma/tratamiento farmacológico , MicroARNs/genética , MicroARNs/metabolismo , Humanos , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Animales , Ratones , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones DesnudosRESUMEN
The RNA-binding protein LIN28B regulates developmental timing and determines stem cell identity by suppressing the let-7 family of microRNAs. Postembryonic reactivation of LIN28B impairs cell commitment to differentiation, prompting their transformation. In this study, we assessed the extent to which ectopic lin28b expression modulates the physiological behavior of neural crest cells (NCC) and governs their transformation in the trunk region of developing embryos. We provide evidence that the overexpression of lin28b inhibits sympathoadrenal cell differentiation and accelerates NCC migration in two vertebrate models, Xenopus leavis and Danio rerio. Our results highlight the relevance of ITGA5 and ITGA6 in the LIN28B-dependent regulation of the invasive motility of tumor cells. The results also establish that LIN28B overexpression supports neuroblastoma onset and the metastatic potential of malignant cells through let-7a-dependent and let-7a-independent mechanisms.
Asunto(s)
Movimiento Celular , Cresta Neural/citología , Proteínas de Unión al ARN/metabolismo , Células Madre/metabolismo , Sistema Simpatoadrenal/citología , Torso/fisiología , Proteínas de Xenopus/metabolismo , Proteínas de Pez Cebra/metabolismo , Animales , Diferenciación Celular , Línea Celular Tumoral , Transición Epitelial-Mesenquimal , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Adhesiones Focales/metabolismo , Humanos , Integrinas/metabolismo , Neuronas/citología , Neuronas/metabolismo , Fenotipo , Transducción de Señal , Xenopus laevis , Pez CebraRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.