RESUMEN
Aberrant expression of the pluripotency factor OCT4A in embryonal tumors of the central nervous system (CNS) is a key factor that contributes to tumor aggressiveness and correlates with poor patient survival. OCT4A overexpression has been shown to up-regulate miR-367, a microRNA (miRNA) that regulates pluripotency in embryonic stem cells and stem-like aggressive traits in cancer cells. Here, we show that (a) miR-367 is carried in microvesicles derived from embryonal CNS tumor cells expressing OCT4A; and (b) inhibition of miR-367 in these cells attenuates their aggressive traits. miR-367 silencing in OCT4A-overexpressing tumor cells significantly reduced their proliferative and invasive behavior, clonogenic activity, and tumorsphere generation capability. In vivo, targeting of miR-367 through direct injections of a specific inhibitor into the cerebrospinal fluid of Balb/C nude mice bearing OCT4A-overexpressing tumor xenografts inhibited tumor development and improved overall survival. miR-367 was also shown to target SUZ12, one of the core components of the polycomb repressive complex 2 known to be involved in epigenetic silencing of pluripotency-related genes, including POU5F1, which encodes OCT4A. Our findings reveal possible clinical applications of a cancer stemness pathway, highlighting miR-367 as a putative liquid biopsy biomarker that could be further explored to improve early diagnosis and prognosis prediction, and potentially serve as a therapeutic target in aggressive embryonal CNS tumors.
Asunto(s)
Biomarcadores de Tumor , Neoplasias del Sistema Nervioso Central , Silenciador del Gen , MicroARNs , Neoplasias de Células Germinales y Embrionarias , Células Madre Neoplásicas , ARN Neoplásico , Animales , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/patología , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/metabolismo , Neoplasias de Células Germinales y Embrionarias/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , ARN Neoplásico/antagonistas & inhibidores , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
To explore the hypothesis that air pollution promotes cardiovascular changes, Swiss mice were continuously exposed, since birth, in two open-top chambers (filtered and nonfiltered for airborne particles Asunto(s)
Envejecimiento/fisiología
, Contaminantes Atmosféricos/efectos adversos
, Contaminación del Aire/efectos adversos
, Ciudades
, Vasos Coronarios/patología
, Exposición por Inhalación/efectos adversos
, Material Particulado/efectos adversos
, Animales
, Brasil
, Colágeno/análisis
, Tejido Elástico/patología
, Fibrosis/patología
, Masculino
, Ratones
, Ratones Endogámicos
, Tamaño de la Partícula
, Factores de Tiempo
, Pruebas de Toxicidad Crónica
, Túnica Íntima/patología
, Túnica Media/patología
RESUMEN
RATIONALE: Chronic exposure to air pollution has been associated with adverse effects on children's lung growth. OBJECTIVES: We analyzed the effects of chronic exposure to urban levels of particulate matter (PM) on selected phases of mouse lung development. METHODS: The exposure occurred in two open-top chambers (filtered and nonfiltered) placed 20 m from a street with heavy traffic in São Paulo, 24 hours/day for 8 months. There was a significant reduction of the levels of PM(2.5) inside the filtered chamber (filtered = 2.9 +/- 3.0 microg/m(3), nonfiltered = 16.8 +/- 8.3 microg/m(3); P = 0.001). At this exposure site, vehicular sources are the major components of PM(2.5) (PM Asunto(s)
Contaminantes Atmosféricos/efectos adversos
, Exposición por Inhalación/efectos adversos
, Material Particulado/efectos adversos
, Alveolos Pulmonares
, Animales
, Brasil
, Modelos Animales de Enfermedad
, Femenino
, Masculino
, Ratones
, Alveolos Pulmonares/crecimiento & desarrollo
, Alveolos Pulmonares/patología
, Pruebas de Función Respiratoria
, Población Urbana
, Emisiones de Vehículos