EphA2 receptor is a key player in the metastatic onset of Ewing sarcoma.
EphA2 receptor is a key player in the metastatic onset of Ewing sarcoma.
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DOI：
10.1002/ijc.31405
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发表时间：
2018-09-01
影响因子：
6.4
通讯作者：
Tirado OM
中科院分区：
文献类型：
--
作者：
Garcia-Monclús S;López-Alemany R;Almacellas-Rabaiget O;Herrero-Martín D;Huertas-Martinez J;Lagares-Tena L;Alba-Pavón P;Hontecillas-Prieto L;Mora J;de Álava E;Rello-Varona S;Giangrande PH;Tirado OM
尤文氏肉瘤（ES）是影响儿童和年轻人的第二大常见骨恶性肿瘤，由于转移率高，预后较差。我们的研究小组先前描述了EphA2，一种酪氨酸激酶受体，通过配体依赖的信号传导促进尤文氏肉瘤（ES）细胞的血管生成。现在我们想探索EphA2配体非依赖性活性，它受S897位点磷酸化控制（p-EphA2S897），因为它与几种恶性肿瘤的转移有关。通过反向基因工程，我们研究了EphA2去除或重新引入后的表型变化。采用基因表达芯片技术鉴定EphA2信号通路的关键参与者。小鼠被用来从原位植入的工程细胞复制转移过程。我们建立了胚胎干细胞侵袭性与p-EphA2S897之间的相关性。此外，在EphA2低表达的ES细胞中，EphA2的稳定过表达增强了增殖和迁移，但没有非磷酸化突变体（S987A）。在实验和体内自发转移试验中，EphA2的沉默一致地降低了肿瘤的致瘤性、体外迁移和侵袭以及肺转移的发生率。基因表达芯片揭示了EphA2在细胞信号传导、细胞运动和存活中的作用。siRNA技术敲低ADAM19强烈再现了EphA2沉默后观察到的对细胞迁移的负面影响。总之，我们的研究结果表明，p-EphA2S897与ES的侵袭性相关，因此阻断其功能可能是一种有希望的治疗方法。
Ewing sarcoma (ES) is the second most common bone malignancy affecting children and young adults with poor prognosis due to high metastasis incidence. Our group previously described that EphA2, a tyrosine kinase receptor, promotes angiogenesis in Ewing sarcoma (ES) cells via ligand-dependent signaling. Now we wanted to explore EphA2 ligand-independent activity, controlled upon phosphorylation at S897 (p-EphA2S897), as it has been linked to metastasis in several malignancies. By reverse genetic engineering we explored the phenotypic changes after EphA2 removal or reintroduction. Gene expression microarray was used to identify key players in EphA2 signaling. Mice were employed to reproduce metastatic processes from orthotopically implanted engineered cells. We established a correlation between ES cells aggressiveness and p-EphA2S897. Moreover, stable overexpression of EphA2 in low EphA2 expression ES cells enhanced proliferation and migration, but not a non-phosphorylable mutant (S987A). Consistently, silencing of EphA2 reduced tumorigenicity, migration and invasion in vitro, and lung metastasis incidence in experimental and spontaneous metastasis assays in vivo. A gene expression microarray revealed the implication of EphA2 in cell signaling, cellular movement and survival. ADAM19 knockdown by siRNA technology strongly reproduced the negative effects on cell migration observed after EphA2 silencing. Altogether, our results suggest that p-EphA2S897 correlates with aggressiveness in ES, so blocking its function may be a promising treatment.
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影响因子：
11.1
作者：
Mendoza-Naranjo A;El-Naggar A;Wai DH;Mistry P;Lazic N;Ayala FR;da Cunha IW;Rodriguez-Viciana P;Cheng H;Tavares Guerreiro Fregnani JH;Reynolds P;Arceci RJ;Nicholson A;Triche TJ;Soares FA;Flanagan AM;Wang YZ;Strauss SJ;Sorensen PH
通讯作者：
Sorensen PH
影响因子：
48
作者：
Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
不依赖配体的EPHA2信号传导驱动靶向治疗介导的转移性黑色素瘤表型的采用。
影响因子：
28.2
作者：
Paraiso KH;Das Thakur M;Fang B;Koomen JM;Fedorenko IV;John JK;Tsao H;Flaherty KT;Sondak VK;Messina JL;Pasquale EB;Villagra A;Rao UN;Kirkwood JM;Meier F;Sloot S;Gibney GT;Stuart D;Tawbi H;Smalley KS
通讯作者：
Smalley KS
影响因子：
4.4
作者：
Koch, Heiner;Busto, M. Estela Del Castillo;Kuster, Bernhard
通讯作者：
Kuster, Bernhard