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    Por favor, use este identificador para citar o enlazar este ítem:https://uvadoc.uva.es/handle/10324/47411

    Título
    Differential regulation of microRNA-15a by radiation affects angiogenesis and tumor growth via modulation of acid sphingomyelinase
    Autor
    Rana, Shushan
    Espinosa Diez, Cristina
    Ruhl, Rebecca
    Chatterjee, Namita
    Hudson, Clayton
    Fraile Bethencourt, María EugeniaAutoridad UVA Orcid
    Agarwal, Anupriya
    Khou, Sokchea
    Thomas, Charles R.
    Anand, Sudarshan
    Año del Documento
    2020
    Editorial
    Nature Research
    Descripción
    Producción Científica
    Documento Fuente
    Scientific Reports, 2020, vol. 10, n. 1
    Resumen
    Activation of acid sphingomyelinase (SMPD1) and the generation of ceramide is a critical regulator of apoptosis in response to cellular stress including radiation. Endothelial SMPD1 has been shown to regulate tumor responses to radiation therapy. We show here that the SMPD1 gene is regulated by a microRNA (miR), miR-15a, in endothelial cells (ECs). Standard low dose radiation (2 Gy) upregulates miR-15a and decreases SMPD1 levels. In contrast, high dose radiation (10 Gy and above) decreases miR-15a and increases SMPD1. Ectopic expression of miR-15a decreases both mRNA and protein levels of SMPD1. Mimicking the effects of high dose radiation with a miR-15a inhibitor decreases cell proliferation and increases active Caspase-3 & 7. Mechanistically, inhibition of miR-15a increases inflammatory cytokines, activates caspase-1 inflammasome and increases Gasdermin D, an effector of pyroptosis. Importantly, both systemic and vascular-targeted delivery of miR-15a inhibitor decreases angiogenesis and tumor growth in a CT26 murine colorectal carcinoma model. Taken together, our findings highlight a novel role for miR mediated regulation of SMPD1 during radiation responses and establish proof-of-concept that this pathway can be targeted with a miR inhibitor.
    Materias Unesco
    24 Ciencias de la Vida
    Palabras Clave
    MicroRNA
    Angiogénesis
    Esfingomielinasa ácida
    ISSN
    2045-2322
    Revisión por pares
    SI
    DOI
    10.1038/s41598-020-62621-8
    Patrocinador
    This work was supported by US NIH (grant R01HL137779 and R01HL143803) to S.A
    ASTRO (Grant ID 534775)
    Version del Editor
    https://www.nature.com/articles/s41598-020-62621-8
    Propietario de los Derechos
    © Nature Research
    Idioma
    eng
    URI
    https://uvadoc.uva.es/handle/10324/47411
    Tipo de versión
    info:eu-repo/semantics/publishedVersion
    Derechos
    openAccess
    Aparece en las colecciones
    • DEP06 - Artículos de revista [352]
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    Attribution-NonCommercial-NoDerivatives 4.0 InternacionalLa licencia del ítem se describe como Attribution-NonCommercial-NoDerivatives 4.0 Internacional

    Universidad de Valladolid

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