RESUMO
Targeting self-renewal is an important goal in cancer therapy and recent studies have focused on Notch signalling in the maintenance of stemness of glioma stem cells (GSCs). Understanding cancer-specific Notch regulation would improve specificity of targeting this pathway. In this study, we find that Notch1 activation in GSCs specifically induces expression of the lncRNA, TUG1. TUG1 coordinately promotes self-renewal by sponging miR-145 in the cytoplasm and recruiting polycomb to repress differentiation genes by locus-specific methylation of histone H3K27 via YY1-binding activity in the nucleus. Furthermore, intravenous treatment with antisense oligonucleotides targeting TUG1 coupled with a drug delivery system induces GSC differentiation and efficiently represses GSC growth in vivo. Our results highlight the importance of the Notch-lncRNA axis in regulating self-renewal of glioma cells and provide a strong rationale for targeting TUG1 as a specific and potent therapeutic approach to eliminate the GSC population.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/terapia , RNA Longo não Codificante/metabolismo , Receptor Notch1/metabolismo , Animais , Carcinogênese/genética , Carcinogênese/patologia , Diferenciação Celular/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Éxons/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , MicroRNAs/genética , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neurônios/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Fator de Transcrição YY1/metabolismoRESUMO
PURPOSE: The majority of bowel obstructions in extremely low birth weight (ELBW) neonates are meconium-related ileus (MRI). ELBW neonates with bowel obstruction may recover by conservative treatment, but some do not. Considering the high surgical morbidity rates, unnecessary surgery should be avoided. We sought to identify a reasonable treatment strategy under these conditions. METHODS: ELBW neonates who started to have bowel obstruction with an unclear cause within 14 days of age were enrolled. The study period was from January 2009 to August 2011. The enrolled patients had daily Gastrografin(®) enemas until 14 days of age or until the obstruction resolved. If the obstruction lasted beyond around 14 days of age, the patient underwent surgical intervention. The clinical data of the patients were collected and analyzed. RESULTS: Fourteen patients were enrolled. Twelve patients had MRI, which resolved within 14 days without surgery. Two patients with persistent obstruction underwent surgery, and they were found to have Hirschsprung's disease and ileal volvulus, respectively. CONCLUSION: For ELBW neonates with bowel obstruction of unclear etiology, the early and frequent administration of a Gastrografin(®) enema is reasonable. Surgery should be considered if the obstruction lasts beyond approximately 14 days after birth.
Assuntos
Enema , Doença de Hirschsprung/terapia , Íleus/terapia , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Fatores Etários , Diatrizoato de Meglumina/administração & dosagem , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Feminino , Humanos , Íleus/etiologia , Recém-Nascido , Masculino , Mecônio , Resultado do TratamentoRESUMO
Debaryomyces vanrijiae MH201 produces formate oxidase (FOD) at estimated pI values by native isoelectric focusing of 5.1, 5.4, and 5.9. We cloned and expressed three formate oxidase cDNAs, FOD1, FOD2, and FDO3, of the yeast using Escherichia coli. The open reading frames of FOD1, FOD2, and FDO3 were 1,731 bp long, and encoded 576-amino acid polypeptides with molecular masses of 64,142, 63,794, and 63,836 Da respectively. Expression of FOD1, FOD2, and FOD3 resulted in the production of three isozymes, with pI values of 5.1, 5.9, and 5.9 respectively. Co-expression of FOD1 and FOD2 and of FOD1 and FOD3 resulted in the production of additional isozymes with pI values, of 5.4. The three amino acid sequences of FOD1, FOD2, and FOD3 contained a consensus motif of a flavin adenine dinucleotide binding site in their N-terminal parts and a glucose-methanol-choline oxidoreductase signature pattern, suggesting that formate oxidase ought to be classified in the glucose-methanol-choline oxidoreductase family.