RESUMO
Glioblastoma (GBM) is the most common primary brain tumor, with poor prognosis and a lack of effective therapeutic options. The aberrant expression of transcription factor REST (repressor element 1-silencing transcription factor) had been reported in different kinds of tumors. However, the function of REST and its mechanisms in GBM remain elusive. Here, REST expression was inhibited by siRNA silencing in U-87 and U-251 GBM cells. Then CCK-8 assay showed significantly decreased cell proliferation, and the inhibition of migration was verified by scratch wound healing assay and transwell assay. Using cell cycle analysis and Annexin V/PI straining assay, G1 phase cell cycle arrest was found to be a reason for the suppression of cell proliferation and migration upon REST silencing, while apoptosis was not affected by REST silencing. Further, the detection of REST-downstream genes involved in cytostasis and migration inhibition demonstrated that CCND1 and CCNE1 were reduced; CDK5R1, BBC3, EGR1, SLC25A4, PDCD7, MAPK11, MAPK12, FADD and DAXX were enhanced, among which BBC3 and DAXX were direct targets of REST, as verified by ChIP (chromatin immunoprecipitation) and Western blotting. These data suggested that REST is a master regulator that maintains GBM cells proliferation and migration, partly through regulating cell cycle by repressing downstream genes, which might represent a potential target for GBM therapy.
Assuntos
Movimento Celular , Proliferação de Células , Glioblastoma/metabolismo , Proteínas Repressoras/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Proteínas Correpressoras , Ciclina D1/genética , Ciclina D1/metabolismo , Ciclina E/genética , Ciclina E/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Proteína de Domínio de Morte Associada a Fas/genética , Proteína de Domínio de Morte Associada a Fas/metabolismo , Fase G1 , Humanos , Proteínas de Membrana Transportadoras , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Chaperonas Moleculares , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/genéticaRESUMO
OBJECTIVE: The aim of the current meta-analysis was to assess the influence of common genetic polymorphisms in the 5-HTR2A gene on the efficacy of antidepressants in the treatment of major depressive disorder (MDD). METHOD: MEDLINE (1966-2013), Cochrane Library Database (Issue 12, 2013), EMBASE (1980-2013), CINAHL (1982-2013), Web of Science (1945-2013) and Chinese Biomedical Database (CBM) (1982-2013) were searched without language restrictions. Meta-analysis was performed using the STATA statistical software. We calculated the odds ratio (OR) and its 95% confidence interval (95% CI) to estimate the efficacy of antidepressants in the treatment of MDD. RESULTS: Eleven studies with a total of 1775 MDD patients met the inclusion criteria of this meta-analysis. Three common polymorphisms in the 5-HTR2A gene were assessed, including rs6311 C>T, rs7997012 G>A, and rs6313 T>C. Our findings suggested that the 5-HTR2A rs6313 T>C polymorphism was significantly correlated with a higher response rate to antidepressants in MDD patients (allele model: OR=1.33, 95% CI=1.05-1.68, P=0.020; dominant model: OR=1.62, 95% CI=1.21-2.18, P=0.001; homozygous model: OR=1.85, 95% CI=1.18-2.90, P=0.008). The rs7997012 G>A polymorphism was also associated with a higher response rate to antidepressants in MDD patients under the dominant model (OR=1.92, 95% CI=1.02-3.61, P=0.044). However, no significant correlation was found for the 5-HTR2A rs6311 C>T polymorphism under five genetic models (all P>0.05). CONCLUSION: Our findings provide empirical evidence that the 5-HTR2A rs6313 T>C and rs7997012 G>A polymorphism may be correlated with the efficacy of antidepressants in the treatment of MDD.