RESUMO
Solid malignancies contain subsets of multipotent cells that grow as spheres and efficiently propagate tumors in xenograft models, reflecting a stem-like, self-renewing and tumor-propagating phenotype. These cancer 'stem cells (SCs)' have been shown to maintain tumor growth, contribute to resistance and drive tumor recurrence. Cancer cell stemness is dynamically influenced by epigenetic mechanisms and differentially regulated coding and noncoding RNAs. How these mechanisms specifically contribute to the generation and/or maintenance of cancer SCs remains unclear. This study identifies a novel epigenetically regulated circuit that integrates microRNA, chromatin remodeling and the reprogramming transcription factor Sox2 to regulate glioblastoma (GBM)-propagating SCs. We show that miR-296-5p expression is repressed in a DNA methylation-dependent manner under conditions that promote GBM cell stemness and that miR-296-5p inhibits GBM cell stemness and their capacity to self-renew as spheres and propagate glioma xenografts in vivo. We show that the chromatin remodeling protein HMGA1 functions as a downstream effector of these biological responses to miR-296-5p and regulates Sox2 expression, a master driver of cell stemness, by modifying chromatin architecture at the Sox2 promoter. These results show for the first time that miR-296-5p inhibits transcriptional mechanisms that support GBM SCs and identify a miR-296-5p:HMGA1:Sox2 axis as a novel regulator of GBM SCs and candidate pathway for targeting therapies directed at depleting tumors of their tumor-propagating stem cell subsets.
Assuntos
Metilação de DNA/genética , Glioblastoma/genética , Proteína HMGA1a/genética , MicroRNAs/genética , Fatores de Transcrição SOXB1/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Montagem e Desmontagem da Cromatina/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Camundongos , Células-Tronco Neoplásicas/patologia , Regiões Promotoras Genéticas , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Consumo de Bebidas Alcoólicas , Comportamento Alimentar , Fumar , Transtornos Relacionados ao Uso de Substâncias , Adolescente , Consumo de Bebidas Alcoólicas/prevenção & controle , Consumo de Bebidas Alcoólicas/psicologia , Criança , Dinamarca , Comportamento Alimentar/fisiologia , Comportamento Alimentar/psicologia , Educação em Saúde , Humanos , Fumar/psicologia , Prevenção do Hábito de Fumar , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle , Transtornos Relacionados ao Uso de Substâncias/psicologiaRESUMO
Minor physical anomalies (MPA) result from disruptions of gestation, and may be used as signs of central nervous system defects in development. Utilizing a Danish birth cohort, we tested the hypothesis that MPA predict adolescent and adult recidivistic violent criminal behavior. The number of MPA was measured at 11 to 13 years of age and police records of criminal behavior were ascertained at 20 to 22 years of age. Recidivistic violent offenders evidenced an elevated level of MPA compared with subjects with one violent offense or subjects with no violent offenses.