Kim M, Jang K, Miller P, Picon-Ruiz M, Yeasky T M, El-Ashry D, Slingerland J M
Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
Oncogene. 2017 Sep 7;36(36):5199-5211. doi: 10.1038/onc.2017.4. Epub 2017 May 15.
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.
癌症干细胞（CSC）似乎具有更强的转移潜能，但其潜在机制仍不清楚。在此我们表明，VEGFA诱导Sox2可促进上皮-间质转化（EMT）和肿瘤转移。在乳腺癌细胞系和原发性癌症培养物中，VEGFA迅速上调SOX2表达，导致SNAI2的诱导、EMT、侵袭和转移增加。我们发现Sox2下调miR-452，miR-452作为一种新型转移抑制因子直接靶向SNAI2的3'-非翻译区（3'-UTR）。VEGFA刺激Sox2和Slug依赖的细胞侵袭。VEGFA在体内增加肺转移，而miR-452过表达可消除这种作用。此外，SNAI2转导可挽救miR-452对转移的抑制作用。因此，除了其血管生成作用外，VEGFA上调Sox2以驱动干细胞扩增，同时miR-452缺失和Slug上调，为癌症干细胞获得转移潜能提供了一种新机制。先前的研究表明EMT转录因子过表达会上调CSC。目前的研究表明干性和转移是一条双向道路：Sox2作为CSC自我更新的主要调节因子，也控制着转移过程。
