Chromosome 1p loss of heterozygosity (LOH) is one of the most frequent cytogenetic aberrations in NB, and this chromosomal region has been scrutinized for putative tumor suppressor genes. In a search for genes regulating neuroblastoma differentiation, we identified a zinc finger gene, hCas, whose drosophila homolog regulates neurogenesis. hCas maps to chromosome 1p36 by FISH, and there is LOH and/or complete deletion of hCas in NB cell lines (8/8) and primary NB tumors (3/3). During normal human fetal development hCas expression peaks at a time comparable to its expression in drosophila, and at a time when migrating neuroblasts form the sympathetic ganglia and the medullary cells of the adrenal glands. In the retinoic acid (RA) induced NB differentiation model, hCas mRNA transiently increases and peaks after 24 hours of RA treatment. The RA-induced increase in hCas mRNA is inversely correlated with a decrease in expression of the N-myc oncogene. In 8/9 NB cell lines there is an inverse correlation between endogenous hCas and N-myc expression (R=-0.894). Decrease in hCas by anti-sense hCas does not change N-myc levels. However, N-myc transfection and overexpression in NB cells consistently decreases hCas expression. Transient transfection of N-myc decreases hCas promoter activity while transfection of a dominant negative N-myc stimulates hCas promoter activity. Thus N-myc negatively regulates hCas. A model in which one allele of hCas is deleted on 1p and the other allele is transcriptionaly silenced by the N-myc oncogene points to a potential mechanism by which two important genetic events in NB, N-myc amplification and 1p LOH, may contribute to tumorigenesis. hCas involvement in both drosophila and human neural development and its expression in NB differentiation raise the possibility that hCas may be a putative NB tumor suppressor gene on 1p.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]