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De novo Identification of MIZ-1 (ZBTB17) Encoding a MYC-Interacting Zinc-Finger Protein as a New Favorable Neuroblastoma Gene

Authors' Affiliations: ¹ Department of Anatomy and Cell Biology, College of Medicine, The University of Illinois at Chicago, Chicago, Illinois; ² Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kamigyo-ku, Kyoto, Japan; Divisions of ³ Neurology, ⁴ Biostatistics, and ⁵ Nucleic Acid Protein Core, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; ⁶ AFLAC Cancer Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia; and ⁷ The Children's Hospital of Los Angeles, Los Angeles, California

Requests for reprints: Xao X. Tang, 808 S. Wood Street, Room 578 CME (MC 512), Chicago, IL 60612. Phone: 312-413-1834; Fax: 312-413-0354; E-mail: xaotang{at}uic.edu.

Purpose: Neuroblastoma is a childhood cancer that exhibits either a favorable or an unfavorable phenotype. Favorable neuroblastoma genes (EPHB6, EFNB2, EFNB3, NTRK1, and CD44) are genes whose high-level expression predicts favorable neuroblastoma disease outcome. Accordingly, the forced expression of these genes or their reactivation by gene silencing inhibitors in unfavorable neuroblastoma cells results in suppression of tumor growth and metastases. This study was undertaken to design an experimental strategy to identify additional favorable neuroblastoma genes.

Experimental Design: Favorable neuroblastoma gene candidates were first identified by gene expression profiling analysis on IMR5 neuroblastoma cells treated with inhibitors of DNA methylation and histone deacetylase against the untreated control cells. Among the candidates, we focused on MIZ-1, which encodes a MYC-interacting zinc-finger protein, because it is known to enhance the expression of growth suppressive genes, such as CDKN1A.

Results: High-level MIZ-1 expression was associated with favorable disease outcome of neuroblastoma (P = 0.0048). Forced MIZ-1 expression suppressed in vitro growth of neuroblastoma cell lines. High MIZ-1 expression was correlated with the small-size neuroblastoma xenografts treated with gene silencing inhibitors or a glucocorticoid. In addition, forced MIZ-1 expression enhanced the expression of CD44 and EFNB2 in neuroblastoma cell lines in vitro. Furthermore, MIZ-1 expression was positively correlated with the expression of favorable neuroblastoma genes (EFNB2, EFNB3, EPHB6, and NTRK1) in the human neuroblastoma xenograft therapeutic models.

Conclusion: MIZ-1 is a new favorable neuroblastoma gene, which may directly or indirectly regulate the expression of other favorable neuroblastoma genes.