Inhibition of tumor growth and metastasis in vitro and in vivo by targeting macrophage migration inhibitory factor in human neuroblastoma

Autor: Yi Ren, Paul K.H. Tam, Jianqing Fan, W Li, Y Xie, G P Jiang, Hiu Man Chan, Y X Chen, Q Liu, Andreas Meinhardt
Rok vydání: 2006
Předmět:
Cancer Research
medicine.medical_specialty
animal diseases
Blotting
Western
Gene Expression
chemical and pharmacologic phenomena
Apoptosis
Enzyme-Linked Immunosorbent Assay
Biology
In Vitro Techniques
medicine.disease_cause
Transfection
DNA
Antisense
Proto-Oncogene Proteins c-myc
Mice
Neuroblastoma
Downregulation and upregulation
Internal medicine
Cell Line
Tumor
otorhinolaryngologic diseases
Genetics
medicine
Animals
Humans
Neoplasm Metastasis
Molecular Biology
Macrophage Migration-Inhibitory Factors
Cell Proliferation
Oligonucleotide Array Sequence Analysis
Receptors
Eph Family
Oncogene
Neovascularization
Pathologic
Cell growth
Brain Neoplasms
Reverse Transcriptase Polymerase Chain Reaction
Receptor Protein-Tyrosine Kinases
Neoplasms
Experimental
respiratory system
Proto-Oncogene Proteins c-met
medicine.disease
biological factors
Endocrinology
Cell culture
Cancer research
Macrophage migration inhibitory factor
Carcinogenesis
Zdroj: Oncogene. 25(25)
ISSN: 0950-9232
Popis: 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.
Databáze: OpenAIRE
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