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Correlation of two distinct metastasis-associated proteins, MTA1 and S100A4, in angiogenesis for promoting tumor growth.
- Source :
-
Oncogene [Oncogene] 2019 Jun; Vol. 38 (24), pp. 4715-4728. Date of Electronic Publication: 2019 Feb 11. - Publication Year :
- 2019
-
Abstract
- Extensive studies on metastasis-associated proteins, S100A4 and MTA1, have been carried out for over two decades, but correlation of both proteins remains obscure. Here we show evidence for the correlation in angiogenesis. First, silencing of each protein by siRNA-mediated knockdown in mouse endothelial MSS31 cells resulted in the inhibition of tube formation. Unexpectedly, the knockdown of MTA1 affected not only its own expression but also the expression of S100A4, whereas silencing of S100A4 did not affect the MTA1 expression. Additionally, non-muscle myosin IIA (NMIIA) phosphorylation, which was partly controlled by S100A4, was found to be upregulated by knockdown of both proteins in MSS31 cells. Moreover, cycloheximide treatment of MSS31 cells revealed that the rate of S100A4 degradation was accelerated by MTA1 knockdown. This finding, together with our observation that cytoplasmic MTA1, but not nuclear MTA1, was colocalized with S100A4, suggested the involvement of MTA1 in S100A4 stability. The direct in vivo angiogenesis assay showed that both protein siRNAs provoked a significant inhibition of new blood vessel formation induced by angiogenic factors, indicating their anti-angiogenic activities. Treatment of human pancreatic tumor (PANC-1) xenograft in mice with mMTA1 siRNA resulted in tumor regression via suppression of angiogenesis in vivo, as also observed in the case of human prostate cancer xenograft treated with mS100A4 siRNA. Taken together, these data led us to conclude that the MTA1-S100A4-NMIIA axis exists in endothelial cells as a novel pathway in promoting tumor vascular formation and could be a target for suppressing tumor growth and metastasis.
- Subjects :
- Animals
Cell Proliferation genetics
Cells, Cultured
Histone Deacetylases genetics
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Knockout
Mice, Nude
Neoplasm Metastasis
Neoplasms genetics
Repressor Proteins genetics
S100 Calcium-Binding Protein A4 genetics
Trans-Activators
Histone Deacetylases physiology
Neoplasms blood supply
Neoplasms pathology
Neovascularization, Pathologic genetics
Repressor Proteins physiology
S100 Calcium-Binding Protein A4 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 38
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 30745574
- Full Text :
- https://doi.org/10.1038/s41388-019-0748-z