SIGNAL TRANSDUCTION OF TRK-FAMILY RECEPTORS IN HUMAN NEUROBLASTOMA

神经母细胞瘤是儿童常见的恶性实体瘤之一。trk家族受体（TRK-A、TRK-B和TRK-C）是神经营养因子（NGF、BDNF、NT-3和NT-4/5）的受体。然而，这些trk家族受体在NBs中的功能和信号转导途径知之甚少。本研究探讨了NBs中TRK-A和TRK-B受体的信号转导途径及其生物学和临床意义，得到以下结果：通过TRK-A受体的信号转导途径：1)NGF的信号转导在1株NB细胞系中介导到细胞核c-fos基因，而在3株NB细胞系中该信号转导在其转导过程中被阻断。2)在NB肿瘤组织（n=24）中，NGF的信号转导在早期肿瘤中介导（13/14例，93%）。3)晚期肿瘤的信号转导或NGF介导较少（6/10例，60%）。通过TRK-B受体的信号转导途径。1) TRK-B在NB细胞系中表达较少。在本研究中，使用指定的表达TRK-B的MP-N-TS的NB细胞系。2)在信号转导中，一个TRK-B、shc、ERK-1和ERK-2的酪氨酸磷酸化被BDNF和NT-4/5增加或诱导，并介导到核c-fos基因中。3)因此，TRK-B的信号转导通过MAP激酶级联介导进入核c-fos基因。通过TRK-A和TRK-B受体的信号转导有助于阐明NB患者的生物学和临床特征。

Neuroblastoma (NB) is one of the common malignant solid tumors in childhood. TRK-family receptors (TRK-A, TRK-B and TRK-C) are the receptors for neurotrophins (NGF, BDNF, NT-3 and NT-4/5). However, little is known about the functions and signal transduction pathways of these TRK-family receptors in NBs. In this study, the signal transduction pathways and biological and clinical significance of TRK-A and TRK-B receptors in NBs were investigated and following results were obtained.1. Signal transduction pathways through TRK-A receptors:1) The signal, transduction of NGF was mediated to the nuclear c-fos gene in one NB cell line, whereas this transductions was blocked in three NB cell lines during their pathways.2) In NB tumor tissues (n=24) the signal transdutions of NGF were mediated in early stage tumors(13/14 cases; 93%).3) However the signal transdutions or NGF were less mediated in advanced stage tumors (6/10 cases; 60%).2. Signal transduction pathways through TRK-B receptors.1) The expressing of TRK-B is rare in NB cell lines. In this study an NB cell line, designated MP-N-TS expressing TRK-B was used.2) In signal transduction, the tyrosine phosphorylation of a TRK-B, shc, ERK-1 and ERK-2 was increased or induced by BDNF and NT-4/5, and mediated into the nuclear c-fos gene.3) Thus, the signal transducton of TRK-B was mediated through MAP kinase cascades and into the nuclear c-fos gene.The signal transductions through TRK-A and TRK-B receptors can be useful to clarify the biological and clinical characteristics of patients with NB.