miR-519d Promotes Melanoma Progression by Downregulating EphA4
miR-519d Promotes Melanoma Progression by Downregulating EphA4
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DOI：
10.1158/0008-5472.can-17-1933
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发表时间：
2018-01-01
期刊：
影响因子：
11.2
通讯作者：
Liao, Yi-Hua
中科院分区：
文献类型：
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作者：
Hua, Kuo-Tai;Hong, Jin-Bong;Liao, Yi-Hua
越来越多的证据表明，在黑色素瘤中有一个独特的细胞亚群，可以在无血清干细胞培养基中形成非粘附性黑色素球，模拟侵袭性恶性肿瘤。使用黑素球作为模型来研究进展机制，我们发现miR-519 d过表达足以促进体外细胞增殖、迁移、侵袭和粘附以及体内肺转移能力。细胞粘附受体EphA 4被确定为miR-519 d的直接靶标。EphA 4的强制表达逆转了miR-519 d过表达的作用，而EphA 4的沉默表型模仿了miR-519 d的作用。恶性进展表型也在上皮-间充质转化水平受到影响，并且ERK 1/2信号通路受到miR-519 d或EphA 4表达的负向影响。在转移性黑色素瘤的临床标本中，我们观察到miR-519 d的显著上调和EphA 4的下调，在后一种情况下与总生存率呈负相关。综上所述，我们的结果表明miR-519 d在决定EphA 4表达和黑色素瘤进展中具有重要的功能作用。(C)2017年AACR。
Increasing evidence suggests that there is a unique cell sub-population in melanoma that can form nonadherent melanospheres in serum-free stem cell medium, mimicking aggressive malignancy. Using melanospheres as a model to investigate progression mechanisms, we found that miR-519d overexpression was sufficient to promote cell proliferation, migration, invasion, and adhesion in vitro and lung metastatic capability in vivo. The cell adhesion receptor EphA4 was determined to be a direct target of miR-519d. Forced expression of EphA4 reversed the effects of miR-519d overexpression, whereas silencing of EphA4 phenocopied the effect of miR-519d. Malignant progression phenotypes were also affected at the level of epithelial-to-mesenchymal transition and the ERK1/2 signaling pathway inversely affected by miR-519d or EphA4 expression. In clinical specimens of metastatic melanoma, we observed significant upregulation of miR-519d and downregulation of EphA4, in the latter case correlated inversely with overall survival. Taken together, our results suggest a significant functional role for miR-519d in determining EphA4 expression and melanoma progression. (C) 2017 AACR.