Role of Nerve Growth Factor Receptor in Differentiation, Maturation and Spontaneous Regression of Human Neuroblastoma

神经生长因子（NGF）在神经嵴细胞的分化、成熟和存活中起重要作用。本研究的目的是探讨神经生长因子、神经生长因子受体、信号传导在人神经母细胞瘤（NB）细胞分化、成熟和自发消退中的作用，最终改善晚期NB患者的不良预后。获得了以下结果。1）trk A NB细胞系中NGF（高亲和力受体）的表达：14株NB细胞中有6株（43%）表达trk A。2）NGF处理后trk A和fos表达：trk A和fos的改变在3个NB细胞系中测定了通过NGF处理的（早期基因）表达，包括一个trk A阴性表达KP-N-RT细胞系，和两个trk阳性表达NB-1和KP-N-SIFA细胞系。KP-N-RT细胞不诱导fos的表达，而NB-1和KP-N-SIFA细胞诱导fos的表达。3）γ-干扰素或维甲酸加NGF处理后trk A和fos的表达：与单独NGF处理相比，γ-干扰素或维甲酸加NGF处理后trk A和fos的表达均增加。Westernblot分析发现trkA蛋白磷酸化。这些结果表明，trk A阳性表达的NB细胞系对NGF有反应，细胞信号可被转导至细胞核内的fos早期基因。因此，通过分析神经生长因子的细胞信号转导，可以区分婴儿NB中观察到的细胞分化、成熟和自发消退，以及儿童NB中观察到的细胞增殖。

Nerve growth factor (NGF) plays an important role in the cell differentiton, maturation and survival of neural crest cells. The purpose of this study is to characterize the function of NGF,NGF receptor, signal transduction in cell differentiation, maturation and spontaneous regression of human neuroblastoma (NB), and eventually to improve the poor prognosis of patients with advanced NB.The following results were obtained.1) trk A (high affinity receptor of NGF) expressions in NB cell lines :The trk A expressions were observed in 6 of 14 NB cell lines (43%).2) trk A and fos expressions by NGF treatment :Alteration of trk A and fos (early gene) expressions by NGF treatment was determined in 3 NB cell lines, including one trk A negative expressing KP-N-RT cell line, and two trk positive expressing NB-1 and KP-N-SIFA cell lines. The expression of fos was not induced in KP-N-RT,whereas these were induced in NB-1 and KP-N-SIFA.3) trk A and fos expressions by gamma-interferon or retinoid folowing by NGF treatment :The expressions of trk A and fos were augmented by either gamma-interferon or retinoid folowing by NGF treatment, as compared with NGF treatment alone. Phosphorylation of trk A protein was observed by Western blot analysis. These resulsts revealed trk A positive expressing NB cell lines could respond to NGF,and cell signal could be transducted into fos early gene in nucleus. This transdution was augmented by gamma-interferon or retinoid treatment.Thus the analysis of cell signal tranduction by NGF may distinguish cell differentiation, maturation and spontaneous regresion observed in infant NB,or cell proliferation observed in child NB.