VEGFA links self-renewal and metastasis by inducing Sox2 to repress miR-452, driving Slug.
VEGFA links self-renewal and metastasis by inducing Sox2 to repress miR-452, driving Slug.
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DOI：
10.1038/onc.2017.4
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发表时间：
2017-09-07
期刊：
影响因子：
8
通讯作者：
Slingerland JM
中科院分区：
文献类型：
--
作者：
Kim M;Jang K;Miller P;Picon-Ruiz M;Yeasky TM;El-Ashry D;Slingerland JM
癌症干细胞（CSC）似乎具有增加的转移潜力，但其潜在机制尚不清楚。在这里，我们表明，VEGFA诱导Sox 2促进EMT和肿瘤转移。在乳腺细胞系和原发性癌症培养物中，VEGFA快速上调SOX 2表达，导致SNAI 2诱导、EMT、增加的侵袭和转移。我们发现Sox 2下调miR-452，miR-452作为一种新的转移抑制因子直接靶向SNAI 2 3′-非翻译区（3′-UTR）。VEGFA刺激Sox 2和Slug依赖性细胞侵袭。VEGFA增加体内肺转移，并且这被miR-452过表达废除。此外，SNAI 2转导通过miR-452挽救转移抑制。因此，除了其血管生成作用外，VEGFA上调Sox 2以驱动干细胞扩增，连同miR-452丢失和Slug上调，提供了癌症干细胞获得转移潜能的新机制。先前的工作表明EMT转录因子过表达上调CSC。目前的工作表明，干细胞和转移是一个双向的街道：Sox 2，CSC自我更新的主要介质，也支配转移过程。
Cancer stem cells (CSC) appear to have increased metastatic potential, but mechanisms underlying this are poorly defined. Here we show that VEGFA induction of Sox2 promotes EMT and tumor metastasis. In breast lines and primary cancer culture, VEGFA rapidly upregulates SOX2 expression, leading to SNAI2 induction, EMT, increased invasion and metastasis. We show Sox2 downregulates miR-452, which acts as a novel metastasis suppressor to directly target the SNAI2 3′-untranslated region (3′-UTR). VEGFA stimulates Sox2- and Slug-dependent cell invasion. VEGFA increases lung metastasis in vivo, and this is abrogated by miR-452 overexpression. Furthermore, SNAI2 transduction rescues metastasis suppression by miR-452. Thus, in addition to its angiogenic action, VEGFA upregulates Sox2 to drive stem cell expansion, together with miR-452 loss and Slug upregulation, providing a novel mechanism whereby cancer stem cells acquire metastatic potential. Prior work showed EMT transcription factor overexpression upregulates CSC. Present work indicates that stemness and metastasis are a two-way street: Sox2, a major mediator of CSC self-renewal, also governs the metastatic process.
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通讯作者：
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