Functions of EPH Receptors and Ephrins in Neuroblastoma

EPH 受体和 Ephrins 在神经母细胞瘤中的功能

• 批准号: 7340889
• 负责人: NAOHIKO IKEGAKI
• 金额: $ 29.15万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7340889
• 关键词: DNA methylation; amidohydrolases; angiogenesis; athymic mouse; cell growth regulation; enzyme activity; ephrins; growth factor receptors; insulinlike growth factor; membrane proteins; metastasis; neoplasm /cancer genetics; neuroblastoma; pediatric neoplasm /cancer; protein structure function; protein tyrosine kinase

DESCRIPTION: (provided by applicant) EPH family receptor protein-tyrosine kinases and ephrin ligands play important roles in neural and cardiovasular development. Our recent study has shown that high-level expression of EPHB6, ephrin-B2, and ephrin-B3 predicts favorable disease outcome of neuroblastoma (NB), a common pediatric tumor of neural crest origin. The goal of this study is to elucidate the underlying mechanisms by which EPHB6, ephrin-B2, and ephrin-B3 provide NB cells with favorable phenotype. EPHIB6 lacks its kinase activity due to a mutation at the ATP acceptor site. Ephrin-B ligands are bi-functional molecules in that their extracellular domains promote angiogenesis and their cytoplasmic domains suppress the growth-promoting activity of activated protein-tyrosine kinases. Based on these observations, we hypothesize that EPHB6 restricts growth, angiogenesis and metastasis of NB cells by acting as a dominant negative member among the EPHB receptor family and/or by sequestering ephrin-B ligands from participating in angiogenesis. Cytoplasmic domains of ephrin-B ligands may inhibit NB growth by suppressing the growth stimulatory effect of receptor tyrosine kinases (IGF1R and TrkA) that are highly expressed by favorable NB. To test these hypotheses, we will examine whether EPHB6 restricts growth, angiogenesis and metastasis of NB cells. We will also examine whether extracellular domains of ephrin-B2 and ephrin-B3, in the absence of EPHB6, facilitate angiogenesis and metastasis of NB and whether EPHB6 blocks the action of ephrin-B ligands in facilitating these processes. We will investigate whether cytoplasmic domains of ephrin-B2 and ephrin-B3 suppress the growth promoting activity of IGF1R and TrkA. Lastly, we will examine whether inhibitors of DNA methylation and histone deacetylation increase EPHB6, ephrin-B2, and ephrin-B3 expressions in unfavorable NB cells, and if so, how these changes affect growth, angiogenesis and metastasis of unfavorable NB cells. Results of this study would reveal novel mechanisms by which EPHB6 and ephrin-B ligands restrict growth, angiogenesis and metastasis of NB. Such knowledge may help develop an innovative and effective treatment for unfavorable NB.

描述：（申请人提供）EPH家族受体蛋白-酪氨酸 激酶和肝配蛋白配体在神经和心血管中发挥重要作用 发展。我们最近的研究表明 EPHB6 的高水平表达， ephrin-B2 和 ephrin-B3 预测神经母细胞瘤的良好疾病结果 （NB），一种常见的神经嵴起源的儿科肿瘤。本研究的目标 目的是阐明 EPHB6、ephrin-B2 和 ephrin-B3 为 NB 细胞提供有利的表型。 EPHIB6 缺乏激酶 由于 ATP 受体位点的突变而产生的活性。 Ephrin-B 配体是 双功能分子，因为它们的细胞外结构域促进 血管生成及其细胞质结构域抑制生长促进 激活的蛋白酪氨酸激酶的活性。根据这些观察，我们 假设 EPHB6 限制 NB 的生长、血管生成和转移 细胞通过充当 EPHB 受体家族中的显性失活成员 和/或通过隔离肝配蛋白-B配体参与血管生成。 肝配蛋白 B 配体的细胞质结构域可能通过抑制 受体酪氨酸激酶（IGF1R 和 TrkA）的生长刺激作用 有利的 NB 高度表达。为了检验这些假设，我们将 检查EPHB6是否限制NB的生长、血管生成和转移 细胞。我们还将检查 ephrin-B2 和 Ephrin-B2 的细胞外结构域是否 ephrin-B3，在缺乏 EPHB6 的情况下，促进血管生成和转移 NB 以及 EPHB6 是否会阻断 ephrin-B 配体促进 这些过程。我们将研究 ephrin-B2 的细胞质结构域是否 ephrin-B3 抑制 IGF1R 和 TrkA 的生长促进活性。最后， 我们将检查 DNA 甲基化和组蛋白脱乙酰化的抑制剂是否 增加不利 NB 细胞中 EPHB6、ephrin-B2 和 ephrin-B3 的表达， 如果是这样，这些变化如何影响肿瘤的生长、血管生成和转移 不利的NB细胞。这项研究的结果将揭示新的机制 EPHB6 和 ephrin-B 配体限制生长、血管生成和转移 的NB。这些知识可能有助于开发创新且有效的治疗方法 对于不利的NB。

项目成果

Biological effects of induced MYCN hyper-expression in MYCN-amplified neuroblastomas.

在 MYCN 扩增的神经母细胞瘤中诱导 MYCN 高表达的生物学效应。

• 发表时间: 2010-10
• 影响因子: 5.2
• 作者: Torres, Jaime;Regan, Paul L;Edo, Robby;Leonhardt, Payton;Jeng, Eric I;Rappaport, Eric F;Ikegaki, Naohiko;Tang, Xao X
• 通讯作者: Tang, Xao X

S(+)-ibuprofen destabilizes MYC/MYCN and AKT, increases p53 expression, and induces unfolded protein response and favorable phenotype in neuroblastoma cell lines.

S( )-ibuprofen 会破坏 MYC/MYCN 和 AKT 的稳定性，增加 p53 表达，并诱导神经母细胞瘤细胞系中的未折叠蛋白反应和有利的表型。

• 发表时间: 2014-01
• 影响因子: 5.2
• 作者: Ikegaki, Naohiko;Hicks, Sakeenah L;Regan, Paul L;Jacobs, Joshua;Jumbo, Amina S;Leonhardt, Payton;Rappaport, Eric F;Tang, Xao X
• 通讯作者: Tang, Xao X