EphA2 as a promoter of melanoma tumorigenicity.
EphA2 as a promoter of melanoma tumorigenicity.
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DOI：
10.4161/cbt.8.3.7485
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发表时间：
2009-02
影响因子：
3.6
通讯作者：
Hess AR
中科院分区：
文献类型：
--
作者：
Margaryan NV;Strizzi L;Abbott DE;Seftor EA;Rao MS;Hendrix MJ;Hess AR
恶性黑色素瘤最大的健康威胁是转移性疾病造成的死亡。因此，识别转移性疾病的标志物对于识别新的治疗靶点是至关重要的。EphA2是一种在上皮细胞中普遍表达的蛋白酪氨酸激酶受体，已被发现在黑色素瘤细胞中过表达并具有结构性活性，其转移表型的特征是侵袭、增殖和血管生成拟态(Vm)增加。基于这一观察，我们假设黑色素瘤肿瘤细胞EphA2表达的增加除了促进整体致瘤性外，还可以促进转移表型的这些特征。我们分析了一组来自患者组织的人黑色素瘤细胞系，这些细胞系被归类为原发期(放射状生长期或垂直生长期)和/或转移性组织，以检测EphA2的表达，发现EphA2表达增加与转移潜力之间存在相关性。使用转移最多的人类黑色素瘤细胞系的实验表明，下调EphA2导致体外侵袭性、增殖性、克隆性和VM显著降低，此外，在原位小鼠模型中，成瘤性也受到抑制。最后，利用人的磷酸化激酶阵列揭示了几种不同的蛋白激酶的磷酸化增加，这些不同的蛋白激酶参与了细胞增殖的各个方面。据我们所知，这些结果提供了第一个直接的体内证据，证明了EphA2在促进黑色素瘤致瘤性方面的作用，并表明EphA2是恶性黑色素瘤治疗干预的重要分子靶点。
The greatest health threat from malignant melanoma is death due to metastatic disease. Consequently, the identification of markers predictive of metastatic disease is essential for identifying new therapeutic targets. EphA2, a protein tyrosine kinase receptor commonly expressed in epithelial cells, has been found to be overexpressed and constitutively active in melanoma tumor cells having a metastatic phenotype as characterized by increased invasion, proliferation and vasculogenic mimicry (VM). Based on this observation, we hypothesized that increased expression of EphA2 by melanoma tumor cells could promote these characteristics of a metastatic phenotype in addition to promoting tumorigenicity as a whole. We analyzed a panel of human melanoma tumor cell lines derived from patient tissues classified as primary (either radial growth phase or vertical growth phase) and/or metastatic for the expression of EphA2 and found a correlation between increased EphA2 expression and metastatic potential. Experiments using the most metastatic of the human melanoma cell lines demonstrated that downregulation of EphA2 results in a significant decrease in invasion, proliferation, clonogenicity and VM in vitro, in addition to suppressed tumorigenicity in an orthotopic mouse model. Lastly, utilization of a human phospho-kinase array revealed increased phosphorylation of several different protein kinases involved in mediating various aspects of cellular proliferation. To the best of our knowledge these results provide the first direct in vivo evidence demonstrating a role for EphA2 in promoting melanoma tumorigenicity and suggest EphA2 as a significant molecular target for the therapeutic intervention of malignant melanoma.
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影响因子：
3.6
作者：
Hess, AR;Seftor, EA;Hendrix, MJC
通讯作者：
Hendrix, MJC
DOI：
10.1007/s00259-007-0503-5
发表时间：
2007-12-01
影响因子：
9.1
作者：
Cai, Weibo;Ebrahimnejad, Alireza;Chen, Xiaoyuan
通讯作者：
Chen, Xiaoyuan
影响因子：
6.5
作者：
EASTY, DJ;GANZ, SE;BENNETT, DC
通讯作者：
BENNETT, DC
影响因子：
5.7
作者：
Kataoka, H;Igarashi, H;Sugimura, H
通讯作者：
Sugimura, H
DOI：
10.1016/j.bbrc.2004.06.054
发表时间：
2004-08-06
影响因子：
3.1
作者：
Duxbury, MS;Ito, H;Whang, EE
通讯作者：
Whang, EE