SIGNAL TRANSDUCTION OF TRK-FAMILY RECEPTORS IN HUMAN NEUROBLASTOMA

人神经母细胞瘤中 TRK 家族受体的信号转导

• 批准号: 10670737
• 负责人: SUGIMOTO Tohru
• 金额: $ 2.05万
• 依托单位: Miyazaki Medical College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670737/
• 关键词: NEUROBLASTOMA; NEUROTROPHIC FACTORS; TRK-FAMILY RECEPTORS; SIGNAL TRANSDUCTION; GROWTH AND DIFFERENTIALTION; TRK-A受容体; TRK-B受容体; 細胞シグナル伝達; 増殖; 分化

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.

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NB中的功能和信号转导途径知之甚少。本研究主要探讨TRK-A和TRK-B受体在NB中的信号转导途径及其生物学和临床意义，并获得以下结果.通过TRK-A受体的信号转导途径：1）在1株NB细胞中，NGF的信号转导是通过核c-fos基因介导的，而在3株NB细胞中，这种信号转导在其通路中被阻断; 2）在NB肿瘤组织（n=24）中，在早期肿瘤中，NGF的信号转导是通过核c-fos基因介导的（13/14例; 93%）; 3）在晚期肿瘤中，NGF的信号转导或NGF的信号转导较少（6/10例; 60%）. TRK-B受体介导的信号转导途径：1）TRK-B在NB细胞系中表达较少。在本研究中，使用了表达TRK-B的NB细胞系，命名为MP-N-TS。2）在信号转导中，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。TRK-B的信号转导是通过MAP激酶级联途径介导的，并进入核c-fos基因，TRK-A和TRK-B的信号转导是通过核c-fos基因介导的。B受体可用于阐明NB患者的生物学和临床特征。

项目成果

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T. Sugimoto 等人：“对神经生长因子、脑源性神经营养因子、神经营养蛋白-3 和神经营养蛋白-4/5 有反应的人神经母细胞瘤细胞系”已提交。

T.Matsumura, T.Sugimoto, et al.: "A neuroblastoma cell line derived from a case detected through a mass screening system in Japan"Cancer. 82. 1416-1417 (1998)

T.Matsumura、T.Sugimoto 等人：“通过日本大规模筛查系统检测到的病例中衍生出的神经母细胞瘤细胞系”癌症。

Y.Horii, H.Kuroda, T.Sugimoto: "Frequent detection of TrkA expression in human neuroblastoma cell lines"Acta Paediatrica Japonica. 40. 644-646 (1986)

Y.Horii、H.Kuroda、T.Sugimoto：“人神经母细胞瘤细胞系中 TrkA 表达的频繁检测”Acta Paediatrica Japonica。

Y. Horii, H. Kuroda, T. Sugimoto: "Frequent detection of TrkA experssion in human neuroblastoma cell lines"Acta Paediatrica Japonica. 40. 644-646 (1986)

Y. Horii、H. Kuroda、T. Sugimoto：“人神经母细胞瘤细胞系中 TrkA 表达的频繁检测”Acta Paediatrica Japonica。