Amplification and over-expression of the N-myc oncogene is associated with the progression of
neuroblastoma in children and in a nude mouse model system.
Neuroblastoma cell lines with widely different levels of N-myc illustrate an inverse relationship between N-myc over-expression and reduced expression of several
integrin extracellular matrix receptors. Transfection and over-expression of N-myc in a
neuroblastoma cell line not normally expressing the
protein resulted in cells that grew loosely associated with tissue culture plates; this correlated with reduced levels of
beta1 integrin subunit. Evidence is now presented that alpha2 and
alpha3 integrin subunit levels are also reduced in cells that over-express N-myc, with virtually no association of alpha2 or alpha3 subunits with beta1. Consequently, maturation of the beta1 subunit and cell surface expression of the
integrins are greatly reduced in N-myc-transfected cells. A small amount of beta1
protein does get to the cell surface, however, suggesting that an as yet unidentified alpha subunit is produced by the N-myc-expressing cells. Finally, the observed reductions in
integrin protein levels are reflections of greatly reduced levels of
integrin alpha2 and alpha3 mRNAs, as well as a smaller reduction in beta1
mRNA (80%, 94% and 52%, respectively). Post-transcriptional mechanisms modulating
beta1 integrin levels are also operative. These results indicate that over-expression of N-myc from a transfected gene in a
neuroblastoma cell line that does not normally produce the
protein generates cell lines with many of the characteristics of naturally metastatic cells with amplified N-myc genes. Modulation of N-myc and
integrin expressions may play a significant role in progression of human
neuroblastoma.