ERBB4 confers metastatic capacity in Ewing sarcoma.
ERBB4 confers metastatic capacity in Ewing sarcoma.
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DOI：
10.1002/emmm.201202343
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发表时间：
2013-07
影响因子：
11.1
通讯作者：
Sorensen PH
中科院分区：
文献类型：
--
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
转移扩散是尤文肉瘤(ES)预后不良的唯一最有力的预测因子。因此，靶向驱动转移的通路在减轻ES的疾病负担方面具有巨大的潜力。我们之前的研究表明，ERBB4酪氨酸激酶的激活可以在体外抑制失巢诱导的细胞死亡，并诱导ES细胞系的化疗耐药。我们现在发现ERBB4在来自化疗耐药或转移性ES肿瘤的ES细胞系中转录水平过表达。ERBB4激活PI3K-Akt级联通路和粘着斑激酶(FAK)，这两条通路在体外和体内都参与了ERBB4介导的rac1 GTPase的激活。ERBB4在体内增强肿瘤的侵袭和转移，这些作用被ERBB4基因敲除所阻断。ERBB4的表达与无瘤生存率的降低显著相关，与原发患者相匹配的ES活检组织相比，转移瘤中ERBB4的表达增加。我们的发现发现了一个与ES侵袭性疾病相关的新的ERBB4-PI3K-Akt-FAK-rac1通路。这些结果表明，ERBB4的治疗靶向，单独或与细胞毒药物联合使用，可能会抑制ES的转移表型。
Metastatic spread is the single-most powerful predictor of poor outcome in Ewing sarcoma (ES). Therefore targeting pathways that drive metastasis has tremendous potential to reduce the burden of disease in ES. We previously showed that activation of the ERBB4 tyrosine kinase suppresses anoikis, or detachment-induced cell death, and induces chemoresistance in ES cell lines in vitro. We now show that ERBB4 is transcriptionally overexpressed in ES cell lines derived from chemoresistant or metastatic ES tumours. ERBB4 activates the PI3K-Akt cascade and focal adhesion kinase (FAK), and both pathways contribute to ERBB4-mediated activation of the Rac1 GTPase in vitro and in vivo. ERBB4 augments tumour invasion and metastasis in vivo, and these effects are blocked by ERBB4 knockdown. ERBB4 expression correlates significantly with reduced disease-free survival, and increased expression is observed in metastatic compared to primary patient-matched ES biopsies. Our findings identify a novel ERBB4-PI3K-Akt-FAK-Rac1 pathway associated with aggressive disease in ES. These results predict that therapeutic targeting of ERBB4, alone or in combination with cytotoxic agents, may suppress the metastatic phenotype in ES.
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影响因子：
3.7
作者：
Mendoza-Naranjo A;Cormie P;Serrano AE;Hu R;O'Neill S;Wang CM;Thrasivoulou C;Power KT;White A;Serena T;Phillips AR;Becker DL
通讯作者：
Becker DL
影响因子：
--
作者：
Cheng H;Clarkson PW;Gao D;Pacheco M;Wang Y;Nielsen TO
通讯作者：
Nielsen TO
影响因子：
3.3
作者：
Chang, Fumin;Lemmon, Christopher A.;Romer, Lewis H.
通讯作者：
Romer, Lewis H.
DOI：
10.1083/jcb.124.4.619
发表时间：
1994-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Frisch SM;Francis H
通讯作者：
Francis H
影响因子：
11.2
作者：
Kang, Hyung-Gyoo;Jenabi, Jasmine M.;Sorensen, Poul H. B.
通讯作者：
Sorensen, Poul H. B.