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Correlation of two distinct metastasis-associated proteins, MTA1 and S100A4, in angiogenesis for promoting tumor growth

Oncogene volume 38, pages 4715–4728 (2019)Cite this article

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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.

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Acknowledgements

We are grateful to Dr. K. Takenaga (Chiba Cancer Center Research Institute, Chiba, Japan) for valuable comments and critical reading of the manuscript. We also thank to Dr. Y. Toh (National Kyushu Cancer Center, Fukuoka, Japan) for valuable information on the MTA1 studies. This work was supported by a grant from the Arteriosclerosis Research Foundation, Tokyo, Japan.

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Authors and Affiliations

  1. Division of Pathological Biochemistry, Department of Biomedical Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan

    Mizuho Ishikawa, Mitsuhiko Osaki, Kunishige Onuma, Hisao Ito & Futoshi Okada

  2. Chromosome Engineering Research Center, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan

    Mitsuhiko Osaki & Futoshi Okada

  3. Laboratory of Tumor Cell Biology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato-ku, Tokyo, 108-8639, Japan

    Makoto Yamagishi

  4. Division of Cellular and Molecular Biology, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, 108-8639, Japan

    Hideya Endo

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  1. Mizuho Ishikawa
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Ishikawa, M., Osaki, M., Yamagishi, M. et al. Correlation of two distinct metastasis-associated proteins, MTA1 and S100A4, in angiogenesis for promoting tumor growth. Oncogene 38, 4715–4728 (2019). https://doi.org/10.1038/s41388-019-0748-z

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