EXPRESSION OF ALTERNATIVELY SPLICED SRC MESSENGER-RNAS RELATED TO NEURONAL DIFFERENTIATION IN HUMAN NEUROBLASTOMAS

Neuroblastoma, the most common malignant solid cancer of children, has an ability to differentiate in vitro and in vivo. This biological pro perty has a significant influence upon the prognosis of patients with neuroblastomas. Neuronal cells express three alternatively spliced for ms of c-src mRNA (nonneuronal c-src, neuronal c-srcN1, and neuronal c- srcN2), which are found at different levels in adult and fetal human b rain tissue. In this study, the transcriptional levels of the three c- src mRNAs were examined in relation to the neural differentiation in e ight human neuroblastoma cell lines and two clonal sublines and in sev en primary neuroblastoma tissues by S1 nuclease protection assays. Neu ronal c-srcN1 mRNA was expressed at high levels in neuroblastoma cell lines with the ability to differentiate but not in the cell lines lack ing the capacity to mature in response to chemical inducers irrespecti ve of N-myc gene amplification and overexpression. In terminally diffe rentiated neuroblastoma cells, the expression of neuronal c-srcN2 mRNA , which was barely detectable at a steady-state level in the uninduced cells, increased to significant levels. Infantile neuroblastomas iden tified by mass screening tests expressed both neuronal c-srcN1 and c-s rcN2 mRNAs at levels almost identical to that found in human brain tis sue, but terminally differentiated neuroblastoma cells, neuroblastomas from older children identified based on clinical symptoms, did not. T hese results suggest that neuronal c-src expression and the ability of neuroblastomas to differentiate in vitro and in vivo may be correlate d.