RESUMEN
Macrophage migration inhibitory factor (MIF) has been defined as a novel oncogene. Our previous results have shown that MIF may contribute to the progression of neuroblastoma by (a) inducing N-Myc expression and (b) upregulating the expression of angiogenic factors. The aim of this study was to test whether tumor growth could be inhibited by reduction of endogenous MIF expression in neuroblastoma and clarify the molecular mechanisms underlying MIF reduction on the control of neuroblastoma growth. We established human neuroblastoma cell lines stably expressing antisense MIF (AS-MIF) cDNA. These stable transfectants were characterized by cell proliferation, gene expression profile, tumorigenicity and metastasis in vitro and in vivo. Decreased MIF expression was observed after transfection with AS-MIF in neuroblastoma cells and downregulation of MIF expression significantly correlated with decreased expression of N-Myc, Ras, c-Met and TrkB at protein level. Affymetrix microarray analysis revealed that expression of IL-8 and c-met was inhibited and neuroblastoma-favorable genes such as EPHB6 and BLU were upregulated in MIF reduced cells. Neuroblastoma cell growth exhibited a nearly 80% reduction in AS-MIF transfectants in vitro. Furthermore, mice in which tumors formed after subcutaneous injection of AS-MIF transfectants showed a 90% reduction in tumor growth compared to control. Metastasis in mice was also suppressed dramatically. Our data demonstrate that targeting MIF expression is a promising therapeutic strategy in human neuroblastoma therapy, and also identifies the MIF target genes for further study.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Proliferación Celular , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Metástasis de la Neoplasia/patología , Neuroblastoma/metabolismo , Animales , Apoptosis/fisiología , Western Blotting , Neoplasias Encefálicas/irrigación sanguínea , Neoplasias Encefálicas/patología , Línea Celular Tumoral , ADN sin Sentido , Ensayo de Inmunoadsorción Enzimática , Expresión Génica , Humanos , Técnicas In Vitro , Ratones , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Neovascularización Patológica/metabolismo , Neuroblastoma/irrigación sanguínea , Neuroblastoma/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas c-met/biosíntesis , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Proteínas Tirosina Quinasas Receptoras/biosíntesis , Receptores de la Familia Eph , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , TransfecciónRESUMEN
Based on the patient's CT/MRI Section images, the brain surgery path Planning system makes surgeon freely draw out the interesting regions through the use of feasible interactive drawing contour function. And by fast judgement, the system is able to give out the risky value of the path. Finally, the system would directly show the surgery path in 3-D display.
