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

Oncogene
M KimJ M Slingerland

Abstract

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.

References

Dec 29, 1989·Biochemical and Biophysical Research Communications·E TischerJ A Abraham
Feb 1, 1997·Endocrine Reviews·N Ferrara, T Davis-Smyth
Jun 5, 2002·Genome Research·W James KentDavid Haussler
Aug 22, 2002·Nature Reviews. Cancer·Jean Paul Thiery
Dec 9, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Daniel J Hicklin, Lee M Ellis
Apr 6, 2005·The Journal of Experimental Medicine·Satoshi HirakawaMichael Detmar
Jun 10, 2005·Nature·Jun LuTodd R Golub
Jun 24, 2005·Nature·Thimmaiah P ChendrimadaRamin Shiekhattar
Aug 16, 2005·Current Opinion in Cell Biology·Margit A HuberHartmut Beug
Sep 13, 2005·Cell·Laurie A BoyerRichard A Young
Apr 25, 2006·Nature Reviews. Molecular Cell Biology·Anna-Karin OlssonLena Claesson-Welsh
Aug 23, 2006·Journal of Mammary Gland Biology and Neoplasia·Arthur M MercurioRobin E Bachelder
Oct 26, 2006·Breast Cancer Research : BCR·Carol SheridanHarikrishna Nakshatri
Dec 5, 2006·Proceedings of the National Academy of Sciences of the United States of America·Kimberly A HartwellRobert A Weinberg
Jan 11, 2007·Clinical Therapeutics·Ted Shih, Celeste Lindley
Jun 1, 2007·Proceedings of the National Academy of Sciences of the United States of America·Sendurai A ManiRobert A Weinberg
Jan 11, 2008·Nature·Sohail F TavazoieJoan Massagué
May 17, 2008·Cancer Research·Tamer T OnderRobert A Weinberg
Aug 7, 2008·PloS One·Anne-Pierre MorelAlain Puisieux
Mar 6, 2009·Nature Reviews. Cancer·Kornelia Polyak, Robert A Weinberg
May 28, 2009·Proceedings of the National Academy of Sciences of the United States of America·Michelle D LarreaJoyce M Slingerland
Jun 3, 2009·The Journal of Clinical Investigation·Raghu Kalluri, Robert A Weinberg
Jul 28, 2009·Annual Review of Medicine·Ramiro GarzonCarlo M Croce
Sep 8, 2009·Nature Medicine·Piyush B GuptaRobert A Weinberg
Nov 26, 2009·Nature Cell Biology·Ulrich WellnerThomas Brabletz
Dec 1, 2009·Cell·Jean Paul ThieryM Angela Nieto

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Citations

May 31, 2018·Non-coding RNA·Almudena Expósito-VillénDiego Franco
Jan 1, 2020·Cancers·Mohammad Hasan SoheilifarZhixiang Wang
Jul 31, 2020·Signal Transduction and Targeted Therapy·Shizhen ZhangYi Sun
Jan 29, 2019·The Journal of Clinical Investigation·Bai CuiQuentin Liu
Mar 1, 2019·Cancers·Shang-Gin WuJin-Yuan Shih
May 31, 2019·Proceedings of the National Academy of Sciences of the United States of America·Emily A IreyKathryn L Schwertfeger
Jun 25, 2020·Cancer Metastasis Reviews·Belinda J Petri, Carolyn M Klinge
Oct 31, 2019·Biological Reviews of the Cambridge Philosophical Society·Goodwin G Jinesh, Andrew S Brohl
Oct 13, 2019·Molecular Therapy : the Journal of the American Society of Gene Therapy·Yujiao ZouZiqing Wu
Jan 20, 2021·Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology·Huilin YangJamie Spangler
Jan 29, 2021·Cancer Communications·Guangtao PanShenglan Yang
Jan 9, 2021·Cell Death & Disease·Sergey ParfenyevNiсkolai A Barlev

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Methods Mentioned

BETA
transfection
PCR
Assay

Software Mentioned

KM
CDS
KM Plotter
R
microT
TargetScan
METABRIC

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