Expression of trkB in human neuroblastoma in relation to MYCN expression and retinoic acid treatment
Expression of trkB in human neuroblastoma in relation to MYCN expression and retinoic acid treatment
复制标题
DOI：
10.1097/01.lab.0000074895.48776.d8
复制
发表时间：
2003-06-01
影响因子：
5
通讯作者：
Påhlman, S
中科院分区：
文献类型：
--
作者：
Edsjö, A;Lavenius, E;Påhlman, S
在一些伴有MYCN基因扩增的高度恶性神经母细胞瘤肿瘤中可发现全长trkB的表达。这与交感神经母细胞形成对比，神经母细胞瘤被认为起源于交感神经母细胞，而交感神经母细胞既不表达trkB，其正常发育也不依赖于p145(trkB)配体、脑源性神经营养因子（BDNF）或神经营养因子 - 4/5。在本研究中，我们发现在5例伴有MYCN扩增的神经母细胞瘤肿瘤中有2例表达trkB，而在一个非MYCN扩增的神经母细胞瘤细胞系中过表达MYCN基因时未观察到trkB表达。这表明MYCN自身过表达不足以诱导trkB表达。全反式维甲酸（RA）可诱导神经母细胞瘤细胞中trkB的表达以及对BDNF的反应性。当用RA和BDNF联合刺激SH - SY5Y细胞时，去甲肾上腺素和酪氨酸羟化酶水平未改变，表明细胞没有向更具儿茶酚胺能的交感神经表型转变。然而，生长相关蛋白43（一种神经元表型的指示物）的表达升高。在RA - BDNF处理的细胞中，囊泡乙酰胆碱转运体、胆碱乙酰转移酶和神经肽酪氨酸的mRNA水平也增加，这可能表明这些细胞发展为交感胆碱能表型。此外，RA处理可诱导血小板衍生生长因子受体 - α的表达。如先前对BDNF所显示的，血小板衍生生长因子刺激了RA处理细胞的生长，这些发现可能具有临床相关性。如果这些受体在体内也介导有丝分裂信号，这可能会限制RA治疗对神经母细胞瘤患者的效果。
Expression of full-length trkB can be found in some highly malignant neuroblastoma tumors with an amplified MYCN gene. This contrasts sympathetic neuroblasts, from which neuroblastomas are thought to arise, which neither express trkB nor are dependent on the p145(trkB) ligands, brain-derived neurotrophic factor (BDNF) or neurotrophin-4/5, for their normal development. In this study we show that trkB was expressed in two out of five neuroblastoma tumors with amplified MYCN, while no trkB expression was observed when the MYCN gene was overexpressed in a non-MYCN-amplified neuroblastoma cell line. This shows that MYCN overexpression per se is not sufficient to induce trkB expression. trkB expression and BDNF responsiveness in neuroblastoma cells can be induced by all-trans-retinoic acid (RA). When SH-SY5Y cells were stimulated with a combination of RA and BDNF, norepinephrine and tyrosine hydroxylase levels were unaltered, showing that the cells did not change toward a more catecholaminergic sympathetic phenotype. However, expression of growth-associated protein 43, indicative of a neuronal phenotype, was elevated. Vesicular acetylcholine transporter, choline acetyl transferase, and neuropeptide tyrosine mRNA levels also increased in RA-BDNF-treated cells, which could suggest that these cells develop into a sympathetic cholinergic phenotype. In addition, treatment with RA-induced expression of the platelet-derived growth factor receptor-alpha. As previously shown for BDNF, platelet-derived growth factor stimulated growth of the RA-treated cells, findings that could have clinical relevance. If these receptors mediate a mitogenic signal in vivo also, this might limit the effect of RA treatment on neuroblastoma patients.