De novo identification of MIZ-1 (ZBTB17) encoding a MYC-interacting zinc-finger protein as a new favorable neuroblastoma gene.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
MIZ-1 is a new favorable neuroblastoma gene, which may directly or indirectly regulate the expression of other favorable neuroblastoma genes.
Ikegaki
Naohiko
N
Department of Anatomy and Cell Biology, College of Medicine, The University of Illinois at Chicago, Chicago, Illinois, USA.
Gotoh
Takahiro
T
Kung
Bing
B
Riceberg
Justin S
JS
Kim
David Y
DY
Zhao
Huaqing
H
Rappaport
Eric F
EF
Hicks
Sakeenah L
SL
Seeger
Robert C
RC
Tang
Xao X
XX
D000818:Animals; D045744:Cell Line, Tumor; D016543:Central Nervous System Neoplasms / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D016896:Treatment Outcome; D016335:Zinc Fingers
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005938:Glucocorticoids; D051741:Kruppel-Like Transcription Factors; D016271:Proto-Oncogene Proteins c-myc; C107961:ZBTB17 protein, human