RESUMO
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.
Assuntos
Biomarcadores Tumorais , Neoplasias do Sistema Nervoso Central , Inativação Gênica , MicroRNAs , Neoplasias Embrionárias de Células Germinativas , Células-Tronco Neoplásicas , RNA Neoplásico , Animais , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Embrionárias de Células Germinativas/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , RNA Neoplásico/antagonistas & inibidores , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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 Assuntos
Envelhecimento/fisiologia
, Poluentes Atmosféricos/efeitos adversos
, Poluição do Ar/efeitos adversos
, Cidades
, Vasos Coronários/patologia
, Exposição por Inalação/efeitos adversos
, Material Particulado/efeitos adversos
, Animais
, Brasil
, Colágeno/análise
, Tecido Elástico/patologia
, Fibrose/patologia
, Masculino
, Camundongos
, Camundongos Endogâmicos
, Tamanho da Partícula
, Fatores de Tempo
, Testes de Toxicidade Crônica
, Túnica Íntima/patologia
, Túnica Média/patologia
RESUMO
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 Assuntos
Poluentes Atmosféricos/efeitos adversos
, Exposição por Inalação/efeitos adversos
, Material Particulado/efeitos adversos
, Alvéolos Pulmonares
, Animais
, Brasil
, Modelos Animais de Doenças
, Feminino
, Masculino
, Camundongos
, Alvéolos Pulmonares/crescimento & desenvolvimento
, Alvéolos Pulmonares/patologia
, Testes de Função Respiratória
, População Urbana
, Emissões de Veículos