Expression of Alternatively Spliced src Messenger RNAs Related to Neuronal Differentiation in Human Neuroblastomas1

Neuroblastoma, the most common malignant solid cancer of children, has an ability to differentiate in vitro and in vivo. This biological property has a significant influence upon the prognosis of patients with neuroblastomas. Neuronal cells express three alternatively spliced forms of c-src mRNA (nonneuronal c-src, neuronal c-srcNl, and neuronal c-srcN2), which are found at different levels in adult and fetal human brain tissue. In this study, the transcriptional levels of the three c-src mRNAs were examined in relation to the neural differentiation in eight human neuro blastoma cell lines and two clonal sublines and in seven primary neuroblastoma tissues by SI nuclease protection assays. Neuronal c-wrM mRNA was expressed at high levels in neuroblastoma cell lines with the ability to differentiate but not in the cell lines lacking the capacity to mature in response to chemical inducers irrespective of N-m.vc gene am plification and overexpression. In terminally differentiated neuroblastoma cells, the expression of neuronal c-srrN2 mRNA, which was barely detect able at a steady-state level in the uninduced cells, increased to significant levels. Infantile neuroblastomas identified by mass screening tests ex pressed both neuronal c-srcNl and c-srcN2 mRNAs at levels almost iden tical to that found in human brain tissue, but terminally differentiated neuroblastoma cells, neuroblastomas from older children identified based on clinical symptoms, did not. These results suggest that neuronal c-src expression and the ability of neuroblastomas to differentiate in vitro and in vivo mav be correlated.