EXPRESSION AND FUNCTION OF TRK-B AND BDNF IN HUMAN NEUROBLASTOMAS
EXPRESSION AND FUNCTION OF TRK-B AND BDNF IN HUMAN NEUROBLASTOMAS
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DOI：
10.1128/mcb.14.1.759
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发表时间：
1994-01-01
影响因子：
5.3
通讯作者：
BRODEUR, GM
中科院分区：
文献类型：
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作者：
NAKAGAWARA, A;AZAR, CG;BRODEUR, GM
TRK家族的神经营养因子受体在调节正常和肿瘤神经细胞的生长和分化中的作用引起了相当大的兴趣。神经母细胞瘤是一种常见的儿科肿瘤，来源于神经嵴，大多数有利的神经母细胞瘤表达高水平的TRK-A mRNA。然而，关于TRK-B在这些肿瘤中的表达或功能知之甚少。TRK-B编码酪氨酸激酶，其结合脑源性神经营养因子（BDNF）以及神经营养因子-3（NT-3）和NT-4/5。我们研究了N-myc扩增的人神经母细胞瘤细胞系SMS-KCN，其表达TRK-B和BDNF。外源性BDNF诱导TRK-B的酪氨酸磷酸化以及磷脂酶C-γ 1、细胞外信号调节激酶1和2以及磷脂酰肌醇-3激酶的磷酸化。BDNF还诱导即刻早期基因c-FOS和NGFI-A的表达，但不诱导NGFI-B或NGFI-C的表达。此外，BDNF似乎促进细胞存活和神经突生长。SMS-KCN细胞还表达TRK-A，其响应于神经生长因子而磷酸化。然而，下游TRK-A信号传导明显有缺陷。最后，我们确定在74例原发性神经母细胞瘤中，36%表达TRK-B mRNA，68%表达BDNF mRNA，31%表达两者。截短的TRK-B似乎优先在分化程度更高的肿瘤（神经节神经瘤和神经节神经母细胞瘤）中表达，而全长TRK-B几乎只在N-myc扩增的未成熟神经母细胞瘤中表达。我们的研究结果表明，在TRK-B表达的人神经母细胞瘤，BDNF促进生存和诱导神经突生长的自分泌或旁分泌的方式。BDNF/TRK-B通路可能对具有N-myc扩增的神经母细胞瘤的生长和分化特别重要。
There is considerable interest in the role of the TRK family of neurotrophin receptors in regulating growth and differentiation in normal and neoplastic nerve cells. A neuroblastoma is a common pediatric tumor derived from the neural crest, and the majority of favorable neuroblastomas express a high level of TRK-A mRNA. However, little is known about the expression or function of TRK-B in these tumors. TRK-B encodes a tyrosine kinase that binds to brain-derived neurotrophic factor (BDNF), as well as neurotrophin-3 (NT-3) and NT-4/5. We have studied the N-myc-amplified human neuroblastoma cell line, SMS-KCN, which expresses both TRK-B and BDNF. Exogenous BDNF induces tyrosine phosphorylation of TRK-B as well as phosphorylation of phospholipase C-gamma1, the extracellular signal-regulated kinases 1 and 2, and phosphatidylinositol-3 kinase. BDNF also induces expression of the immediate-early genes c-FOS and NGFI-A but not NGFI-B or NGFI-C. In addition, BDNF appears to promote cell survival and neurite outgrowth. SMS-KCN cells also express TRK-A, which is phosphorylated in response to nerve growth factor. However, the downstream TRK-A signaling is apparently defective. Finally, we determined that in a series of 74 primary neuroblastomas, 36% express TRK-B mRNA, 68% express BDNF mRNA, and 31% express both. Truncated TRK-B appears to be preferentially expressed in more-differentiated tumors (ganglioneuromas and ganglioneuroblastomas), whereas full-length TRK-B is expressed almost exclusively in immature neuroblastomas with N-myc amplification. Our findings suggest that in TRK-B-expressing human neuroblastomas, BDNF promotes survival and induces neurite outgrowth in an autocrine or paracrine manner. The BDNF/TRK-B pathway may be particularly important for growth and differentiation of neuroblastomas with N-myc amplification.