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

Oncogene volume 25, pages 3501–3508 (2006)Cite this article

A Corrigendum to this article was published on 16 November 2006

Abstract

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.

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Acknowledgements

The research was supported by a grant from the University of Hong Kong (CRCG 10204242/35644/21700/323/01), NIH R01-GM072611 and NSF DMS-0354223.

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Authors and Affiliations

  1. Department of Surgery, The University of Hong Kong, Hong Kong, SAR, China

    Y Ren, H M Chan, Y Xie, Y X Chen, W Li, G P Jiang, Q Liu & P K H Tam

  2. Center for Hematology and Oncology Molecular Therapeutics, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH, USA

    Y Ren

  3. Statistics Laboratory, ORFE, Princeton University, Princeton, NJ, USA

    J Fan

  4. Department of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany

    A Meinhardt

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  1. Y Ren
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Correspondence to Y Ren or P K H Tam.

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Ren, Y., Chan, H., Fan, J. et al. Inhibition of tumor growth and metastasis in vitro and in vivo by targeting macrophage migration inhibitory factor in human neuroblastoma. Oncogene 25, 3501–3508 (2006). https://doi.org/10.1038/sj.onc.1209395

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