Insulin-like growth factor binding protein 5: Contribution to growth and differentiation of neuroblastoma cells
Insulin-like growth factor binding protein 5: Contribution to growth and differentiation of neuroblastoma cells
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DOI：
10.1196/annals.1322.007
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发表时间：
2004-01-01
期刊：
影响因子：
--
通讯作者：
Raschella, G
中科院分区：
文献类型：
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作者：
Cesi, V;Vitali, R;Raschella, G
神经母细胞瘤（NB）是一种依赖胰岛素样生长因子（IGFs）生长和转移扩散的儿童肿瘤。一些转移性NB通过激活IGF-2的自分泌产生而不依赖于IGF的旁分泌支持。胰岛素样生长因子结合蛋白-5（IGFBP-5）是IGF结合蛋白家族的一员，能够优化IGF本身与其受体之间的结合。NB细胞系在用视黄酸（RA）处理后保持体外向神经元、Schwarm样或黑素细胞表型分化的能力。类维生素A目前用于NB治疗以实现成熟的有丝分裂后表型。在这里，我们提出的证据表明，IGFBP-5的表达是神经母细胞瘤细胞系的一个共同特征，IGFBP-5的行为与IGF-2在诱导细胞增殖。RA诱导的分化导致IGFBP-5的急剧增加。在分化条件下进行的功能测定表明IGFBP-5转录对RA治疗敏感。我们发现RA对IGFBP-5启动子的作用至少部分是通过近端5 '-CACCC-3 '串联重复序列（距转录起始位点-147 bp至-137 bp）发挥的，该序列先前被描述为成骨细胞中参与甾酮介导的反应的顺式作用元件。鉴于IGF-2在决定NB的增殖和转移行为中的相关性，IGFBP-5作为IGF信号转导通路的调节剂的作用应进一步研究以用于潜在的治疗应用。
Neuroblastoma (NB) is a childhood tumor that depends on insulin-like growth factors (IGFs) for its growth and metastatic spread. Some metastatic NBs acquire independence from the paracrine support of IGF by activating autocrine production of IGF-2. Insulin-like growth factor binding protein-5 (IGFBP-5), a member of the IGF binding protein family, is able to optimize binding between IGF itself and its receptor. NB cell lines retain the ability to differentiate in vitro toward neuronal, Schwarm-like or melanocytic phenotypes upon treatment with retinoic acid (RA). Retinoids are currently used in NB therapy to achieve a mature postmitotic phenotype. Here, we present evidence that the expression of IGFBP-5 is a common feature of neuroblastoma cell lines and that IGFBP-5 acts in concert with IGF-2 in inducing cell proliferation. RA-induced differentiation causes a sharp increase of IGFBP-5. Functional assays carried out in differentiating conditions demonstrate that IGFBP-5 transcription is sensitive to RA treatment. We show that the effect of RA on the IGFBP-5 promoter is exerted, at least in part, through a proximal 5 '-CACCC-3 ' tandem repeat (-147 bp to -137 bp from the transcription start site) that has previously been described as a cis-acting element involved in the progesterone-mediated response in osteoblasts. Given the relevance of IGF-2 in determining the proliferative and metastatic behavior of NB, the role of IGFBP-5 as a modulator of the IGF signal transduction pathway should be studied further for potential therapeutic applications.