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Hypoxia promotes breast cancer cell invasion through HIF-1α-mediated up-regulation of the invadopodial actin bundling protein CSRP2.
- Source :
-
Scientific reports [Sci Rep] 2018 Jul 05; Vol. 8 (1), pp. 10191. Date of Electronic Publication: 2018 Jul 05. - Publication Year :
- 2018
-
Abstract
- 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-1α-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.
- Subjects :
- Adult
Aged
Animals
Breast pathology
Breast Neoplasms mortality
Breast Neoplasms pathology
Cell Hypoxia
Cell Line, Tumor
Cell Movement
Female
Gene Knockdown Techniques
Humans
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Kaplan-Meier Estimate
LIM Domain Proteins metabolism
Mice
Middle Aged
Muscle Proteins metabolism
Neoplasm Invasiveness pathology
Nuclear Proteins metabolism
Promoter Regions, Genetic
RNA, Small Interfering metabolism
Up-Regulation
Xenograft Model Antitumor Assays
Breast Neoplasms genetics
Extracellular Matrix pathology
Gene Expression Regulation, Neoplastic
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
LIM Domain Proteins genetics
Muscle Proteins genetics
Nuclear Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 8
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 29976963
- Full Text :
- https://doi.org/10.1038/s41598-018-28637-x