PMID- 29976963
OWN - NLM
STAT- MEDLINE
DCOM- 20191028
LR  - 20191028
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 8
IP  - 1
DP  - 2018 Jul 5
TI  - Hypoxia promotes breast cancer cell invasion through HIF-1alpha-mediated 
      up-regulation of the invadopodial actin bundling protein CSRP2.
PG  - 10191
LID - 10.1038/s41598-018-28637-x [doi]
LID - 10191
AB  - Hypoxia is a common feature of solid tumours that promotes invasion and 
      metastatic dissemination. Invadopodia are actin-rich membrane protrusions that 
      direct extracellular matrix proteolysis and facilitate tumour cell invasion. 
      Here, we show that CSRP2, an invadopodial actin bundling protein, is upregulated 
      by hypoxia in various breast cancer cell lines, as well as in pre-clinical and 
      clinical breast tumour specimens. We functionally characterized two hypoxia 
      responsive elements within the proximal promoter of CSRP2 gene which are targeted 
      by hypoxia-inducible factor-1 (HIF-1) and required for promoter transactivation 
      in response to hypoxia. Remarkably, CSRP2 knockdown significantly inhibits 
      hypoxia-stimulated invadopodium formation, ECM degradation and invasion in 
      MDA-MB-231 cells, while CSRP2 forced expression was sufficient to enhance the 
      invasive capacity of HIF-1alpha-depleted cells under hypoxia. In MCF-7 cells, CSRP2 
      upregulation was required for hypoxia-induced formation of invadopodium 
      precursors that were unable to promote ECM degradation. Collectively, our data 
      support that CSRP2 is a novel and direct cytoskeletal target of HIF-1 which 
      facilitates hypoxia-induced breast cancer cell invasion by promoting invadopodia 
      formation.
FAU - Hoffmann, Celine
AU  - Hoffmann C
AD  - Laboratory of Experimental Cancer Research, 84 Val Fleuri, L-1526, Luxembourg, 
      Luxembourg.
FAU - Mao, Xianqing
AU  - Mao X
AD  - Laboratory of Experimental Cancer Research, 84 Val Fleuri, L-1526, Luxembourg, 
      Luxembourg.
FAU - Brown-Clay, Joshua
AU  - Brown-Clay J
AD  - Laboratory of Experimental Cancer Research, 84 Val Fleuri, L-1526, Luxembourg, 
      Luxembourg.
FAU - Moreau, Flora
AU  - Moreau F
AD  - Laboratory of Experimental Cancer Research, 84 Val Fleuri, L-1526, Luxembourg, 
      Luxembourg.
FAU - Al Absi, Antoun
AU  - Al Absi A
AD  - Laboratory of Experimental Cancer Research, 84 Val Fleuri, L-1526, Luxembourg, 
      Luxembourg.
FAU - Wurzer, Hannah
AU  - Wurzer H
AD  - Laboratory of Experimental Cancer Research, 84 Val Fleuri, L-1526, Luxembourg, 
      Luxembourg.
AD  - Faculaty of Science, Technology and Communication, University of Luxembourg, 2 
      avenue de l'Universite, L-4365, Esch-sur-Alzette, Luxembourg.
FAU - Sousa, Barbara
AU  - Sousa B
AD  - IPATIMUP- Institute of Molecular Pathology and Immunology of the University of 
      Porto, Medical Faculty of Porto University, Rua Julio Amaral de Carvalho 45, 
      4200-135, Porto, Portugal.
FAU - Schmitt, Fernando
AU  - Schmitt F
AD  - IPATIMUP- Institute of Molecular Pathology and Immunology of the University of 
      Porto, Medical Faculty of Porto University, Rua Julio Amaral de Carvalho 45, 
      4200-135, Porto, Portugal.
FAU - Berchem, Guy
AU  - Berchem G
AD  - Laboratory of Experimental Cancer Research, 84 Val Fleuri, L-1526, Luxembourg, 
      Luxembourg.
FAU - Janji, Bassam
AU  - Janji B
AUID- ORCID: 0000-0002-9763-0943
AD  - Laboratory of Experimental Cancer Research, 84 Val Fleuri, L-1526, Luxembourg, 
      Luxembourg.
FAU - Thomas, Clement
AU  - Thomas C
AD  - Laboratory of Experimental Cancer Research, 84 Val Fleuri, L-1526, Luxembourg, 
      Luxembourg. Clement.thomas@lih.lu.
LA  - eng
GR  - 7.4512.16/Fonds De La Recherche Scientifique - FNRS (Belgian National Fund for 
      Scientific Research)/International
GR  - PRIDE15/10675146/CANBIO/Fonds National de la Recherche Luxembourg (National 
      Research Fund)/International
GR  - PRIDE15/10675146/CANBIO/Fonds National de la Recherche Luxembourg (National 
      Research Fund)/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180705
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (CSRP2 protein, human)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (LIM Domain Proteins)
RN  - 0 (Muscle Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RNA, Small Interfering)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Animals
MH  - Breast/pathology
MH  - Breast Neoplasms/*genetics/mortality/pathology
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Cell Movement
MH  - Extracellular Matrix/*pathology
MH  - Female
MH  - *Gene Expression Regulation, Neoplastic
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Kaplan-Meier Estimate
MH  - LIM Domain Proteins/*genetics/metabolism
MH  - Mice
MH  - Middle Aged
MH  - Muscle Proteins/*genetics/metabolism
MH  - Neoplasm Invasiveness/pathology
MH  - Nuclear Proteins/*genetics/metabolism
MH  - Promoter Regions, Genetic
MH  - RNA, Small Interfering/metabolism
MH  - Up-Regulation
MH  - Xenograft Model Antitumor Assays
PMC - PMC6033879
COIS- The authors declare no competing interests.
EDAT- 2018/07/07 06:00
MHDA- 2019/10/29 06:00
PMCR- 2018/07/05
CRDT- 2018/07/07 06:00
PHST- 2018/02/08 00:00 [received]
PHST- 2018/06/13 00:00 [accepted]
PHST- 2018/07/07 06:00 [entrez]
PHST- 2018/07/07 06:00 [pubmed]
PHST- 2019/10/29 06:00 [medline]
PHST- 2018/07/05 00:00 [pmc-release]
AID - 10.1038/s41598-018-28637-x [pii]
AID - 28637 [pii]
AID - 10.1038/s41598-018-28637-x [doi]
PST - epublish
SO  - Sci Rep. 2018 Jul 5;8(1):10191. doi: 10.1038/s41598-018-28637-x.