VEGFA links self-renewal and metastasis by inducing Sox2 to repress miR-452, driving Slug

M. Kim, K. Jang, P. Miller, M. Picon-Ruiz, T. M. Yeasky, D. El-Ashry, J. M. Slingerland

Research output: Contribution to journalArticlepeer-review

57 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)5199-5211
Number of pages13
Issue number36
StatePublished - Sep 7 2017

Bibliographical note

Funding Information:
This work was supported by funding from the Breast Cancer Research Foundation to JMS.

Publisher Copyright:
© The Author(s) 2017.


Dive into the research topics of 'VEGFA links self-renewal and metastasis by inducing Sox2 to repress miR-452, driving Slug'. Together they form a unique fingerprint.

Cite this