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VEGFA links self-renewal and metastasis by inducing Sox2 to repress miR-452, driving Slug
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 SNA...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596211/ https://www.ncbi.nlm.nih.gov/pubmed/28504716 http://dx.doi.org/10.1038/onc.2017.4 |
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author | Kim, M Jang, K Miller, P Picon-Ruiz, M Yeasky, T M El-Ashry, D Slingerland, J M |
author_facet | Kim, M Jang, K Miller, P Picon-Ruiz, M Yeasky, T M El-Ashry, D Slingerland, J M |
author_sort | Kim, M |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5596211 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-55962112017-09-14 VEGFA links self-renewal and metastasis by inducing Sox2 to repress miR-452, driving Slug Kim, M Jang, K Miller, P Picon-Ruiz, M Yeasky, T M El-Ashry, D Slingerland, J M Oncogene Original Article 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. Nature Publishing Group 2017-09-07 2017-05-15 /pmc/articles/PMC5596211/ /pubmed/28504716 http://dx.doi.org/10.1038/onc.2017.4 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Kim, M Jang, K Miller, P Picon-Ruiz, M Yeasky, T M El-Ashry, D Slingerland, J M VEGFA links self-renewal and metastasis by inducing Sox2 to repress miR-452, driving Slug |
title | VEGFA links self-renewal and metastasis by inducing Sox2 to repress miR-452, driving Slug |
title_full | VEGFA links self-renewal and metastasis by inducing Sox2 to repress miR-452, driving Slug |
title_fullStr | VEGFA links self-renewal and metastasis by inducing Sox2 to repress miR-452, driving Slug |
title_full_unstemmed | VEGFA links self-renewal and metastasis by inducing Sox2 to repress miR-452, driving Slug |
title_short | VEGFA links self-renewal and metastasis by inducing Sox2 to repress miR-452, driving Slug |
title_sort | vegfa links self-renewal and metastasis by inducing sox2 to repress mir-452, driving slug |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596211/ https://www.ncbi.nlm.nih.gov/pubmed/28504716 http://dx.doi.org/10.1038/onc.2017.4 |
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