Heparin-binding epidermal growth factor-like growth factor promotes neuroblastoma differentiation
Heparin-binding epidermal growth factor-like growth factor promotes neuroblastoma differentiation
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DOI：
10.1096/fj.201600828r
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发表时间：
2017-05-01
期刊：
影响因子：
4.8
通讯作者：
Blobe, Gerard C.
中科院分区：
文献类型：
--
作者：
Gaviglio, Angela L.;Knelson, Erik H.;Blobe, Gerard C.
高危神经母细胞瘤的特征是未分化的神经母细胞和低雪旺氏间质含量。肿瘤间质通过释放促进成神经细胞分化的可溶性因子来抑制肿瘤生长。在这里，我们确定肝素结合表皮生长因子样生长因子（HBEGF）作为一个强大的促分化因子在神经母细胞瘤。与良性肿瘤相比，人神经母细胞瘤中HBEGF mRNA表达降低，其丢失与生存率降低相关。HBEGF蛋白仅在人神经母细胞瘤标本的间质区室中表达，而来自高阶段疾病的组织含有非常少的间质或HBEGF表达。在3种人神经母细胞瘤细胞系（SK-N-AS、SK-N-BE 2和SH-SY 5 Y）中，可溶性HBEGF足以促进神经母细胞分化并降低增殖。硫酸乙酰肝素蛋白聚糖和肝素衍生物通过与表皮生长因子受体形成复合物进一步增强HBEGF诱导的分化，导致ERK 1/2和STAT 3途径的激活和DNA结合转录因子抑制剂的上调。这些数据支持神经母细胞瘤发病机制中神经母细胞瘤肿瘤微环境中HBEGF的丢失。Gaviglio，A. L.，Knelson，E. H、布洛湾C.肝素结合表皮生长因子样生长因子促进神经母细胞瘤分化。
High-risk neuroblastoma is characterized by undifferentiated neuroblasts and low schwannian stroma content. The tumor stroma contributes to the suppression of tumor growth by releasing soluble factors that promote neuroblast differentiation. Here we identify heparin-binding epidermal growth factor-like growth factor (HBEGF) as a potent prodifferentiating factor in neuroblastoma. HBEGF mRNA expression is decreased in human neuroblastoma tumors compared with benign tumors, with loss correlating with decreased survival. HBEGF protein is expressed only in stromal compartments of human neuroblastoma specimens, with tissue from high-stage disease containing very little stroma orHBEGF expression. In 3 human neuroblastoma cell lines (SK-N-AS, SK-N-BE2, and SH-SY5Y), soluble HBEGF is sufficient to promote neuroblast differentiation and decrease proliferation. Heparan sulfate proteoglycans and heparin derivatives further enhance HBEGF-induced differentiation by forming a complex with the epidermal growth factor receptor, leading to activation of the ERK1/2 and STAT3 pathways and up-regulation of the inhibitor of DNA binding transcription factor. These data support a role for loss of HBEGF in the neuroblastoma tumor microenvironment in neuroblastoma pathogenesis.-Gaviglio, A. L., Knelson, E. H., Blobe, G. C. Heparin-binding epidermal growth factor-like growth factor promotes neuroblastoma differentiation.