Ref ID: 355.1

Loss of hCas function, a novel neuroblastoma differentiation related gene, via LOH at chromosome 1p36.22 and functional silencing by N-myc

Xuezhong Yang, Linda Stapleton, Valery Bliskovsky, Gautam Rajpal, Kathleen Cullion, Beverly Mock, Thomas Ried, Carol J Thiele

Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA.

Chromosome 1p deletion (LOH: loss of heterozygosity) 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 both 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 drsophila, and a time when migrating neuroblasts form the sympathetic ganglia and adrenal glands. In the retinoic acid (RA) induced NB differentiation model, hCas mRNA transiently increases and peaks after 24 hours of RA treatment. The 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 hCas and N-myc expression (R=-0.894). Decreases in hCas by anti-sense hCas does not change N-myc levels. However, N-myc transfection and overexpression in NB cells consistently causes decreased hCas expression, thus N-myc negatively regulates hCas. We identified the promoter of hCas, which includes two putative N-myc binding E-boxes. 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. The involvement in both drosophila and human neural development and the expression in NB differentiation raises the possibility that hCas may be a putative NB tumor suppressor gene on 1p.

Presentation mode(s): oral-presentation – pc-projector