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
Alexia and agraphia are disorders common to the left inferior parietal lobule, including the angular and supramarginal gyri. However, it is still unclear how these cortical regions interact with other cortical sites and what the most important white matter tracts are in relation to reading and writing processes. Here, the authors present the case of a patient who underwent an awake craniotomy for a left inferior parietal lobule glioma using direct cortical and subcortical electrostimulation. The use of subcortical stimulation allowed identification of the specific white matter tracts associated with reading and writing. These tracts were found as portions of the dorsal inferior frontooccipital fasciculus (IFOF) fibers in the deep parietal lobe that are responsible for connecting the frontal lobe to the superior parietal lobule. These findings are consistent with previous diffusion tensor imaging tractography and functional MRI studies, which suggest that the IFOF may play a role in the reading and writing processes. This is the first report of transient alexia and agraphia elicited through intraoperative direct subcortical electrostimulation, and the findings support the crucial role of the IFOF in reading and writing.