Article | Published:

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


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Weigelt B, Peterse JL, van’t Veer LJ. Breast cancer metastasis: markers and models. Nat Rev Cancer. 2005;5:591–602.

  2. 2.

    Mehlen P, Puisieux A. Metastasis: a question of life or death. Nat Rev Cancer. 2006;6:449–58.

  3. 3.

    Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, et al. Genes that mediate breast cancer metastasis to lung. Nature. 2005;436:518–24.

  4. 4.

    Hunter K. Host genetics influence tumour metastasis. Nat Rev Cancer. 2006;6:141–6.

  5. 5.

    Riker AI, Enkemann SA, Fodstad O, Liu S, Ren S, Morris C, et al. The gene expression profiles of primary and metastatic melanoma yields a transition point of tumor progression and metastasis. BMC Med Genomics. 2008;1:13.

  6. 6.

    Toh Y, Pencil SD, Nicolson GL. A novel candidate metastasis-associated gene, mta1, differentially expressed in highly metastatic mammary adenocarcinoma cell lines. cDNA cloning, expression, and protein analysis. J Biol Chem. 1994;269:22958–63.

  7. 7.

    Ebralidze A, Tulchinsky E, Grigorian M, Afanasyeva A, Senin V, Revazova E, et al. Isolation and characterization of a gene specifically expressed in different metastatic cells and whose deduced gene product has a high degree of homology to a Ca2+-binding protein family. Genes Dev. 1989;3:1086–93.

  8. 8.

    Jang KS, Paik SS, Chung H, Oh YH, Kong G. MTA1 overexpression correlates significantly with tumor grade and angiogenesis in human breast cancers. Cancer Sci. 2006;97:374–9.

  9. 9.

    Toh Y, Kuwano H, Mori M, Nicolson GL, Sugimachi K. Overexpression of metastasis-associated MTA1 mRNA in invasive esophageal carcinomas. Br J Cancer. 1999;79:1723–6.

  10. 10.

    Zhu X, Guo Y, Li X, Ding Y, Chen L. Metastasis-associated protein 1 nuclear expression is associated with tumor progression and clinical outcome in patients with non-small cell lung cancer. J Thorac Oncol. 2010;5:1159–66.

  11. 11.

    Dannenmann C, Shabani N, Friese K, Jeschke U, Mylonas I, Bruning A. The metastasis-associated gene MTA1 is upregulated in advanced ovarian cancer, represses ER beta, and enhances expression of oncogenic cytokine GRO. Cancer Biol Ther. 2008;7:1460–7.

  12. 12.

    Xue Y, Wong J, Moreno GT, Young MK, Côté J, Wang W. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol Cell. 1998;2:851–61.

  13. 13.

    Toh Y, Kuninaka S, Endo K, Oshiro T, Ikeda Y, Nakashima H, et al. Molecular analysis of a candidate metastasis-associated gene, MTA1: possible interaction with histone deacetylase 1. J Exp Clin Cancer Res. 2000;19:105–11.

  14. 14.

    Yoo YG, Kong G, Lee MO. Metastasis-associated protein 1 enhances stability of hypoxia-inducible factor-1alpha protein by recruiting histone deacetylase 1. EMBO J. 2006;25:1231–41.

  15. 15.

    Moon HE, Cheon H, Chun KH, Lee SK, Kim YS, Jung BK, et al. Metastasis-associated protein 1 enhances angiogenesis by stabilization of HIF-1alpha. Oncol Rep. 2006;16:929–35.

  16. 16.

    Garrett SC, Varney KM, Weber DJ, Bresnick AR. S100A4, a mediator of metastasis. J Biol Chem. 2006;281:677–80.

  17. 17.

    de Silva Rudland S, Martin L, Roshanlall C, Winstanley J, Leinster S, Platt-Higgins A, et al. Association of S100A4 and osteopontin with specific prognostic factors and survival of patients with minimally invasive breast cancer. Clin Cancer Res. 2006;12:1192–1200.

  18. 18.

    Takenaga K, Nakanishi H, Wada K, Suzuki M, Matsuzaki O, Matsuura A, et al. Increased expression of S100A4, a metastasis-associated gene, in human colorectal adenocarcinomas. Clin Cancer Res. 1997;3:2309–16.

  19. 19.

    Wang YY, Ye ZY, Zhao ZS, Tao HQ, Chu YQ. High-level expression of S100A4 correlates with lymph node metastasis and poor prognosis in patients with gastric cancer. Ann Surg Oncol. 2010;17:89–97.

  20. 20.

    Oida Y, Yamazaki H, Tobita K, Mukai M, Ohtani Y, Miyazaki N, et al. Increased S100A4 expression combined with decreased E-cadherin expression predicts a poor outcome of patients with pancreatic cancer. Oncol Rep. 2006;16:457–63.

  21. 21.

    Takenaga K, Nakamura Y, Endo H, Sakiyama S. Involvement of S100-related calcium-binding protein pEL98 (or mts1) in cell motility and tumor cell invasion. Jpn J Cancer Res. 1994;85:831–9.

  22. 22.

    Schmidt-Hansen B, Ornås D, Grigorian M, Klingelhöfer J, Tulchinsky E, Lukanidin E, et al. Extracellular S100A4(mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity. Oncogene. 2004;23:5487–95.

  23. 23.

    Ambartsumian N, Klingelhöfer J, Grigorian M, Christensen C, Kriajevska M, Tulchinsky E, et al. The metastasis-associated Mts1(S100A4) protein could act as an angiogenic factor. Oncogene. 2001;20:4685–95.

  24. 24.

    Ochiya T, Takenaga K, Endo H. Silencing of S100A4, a metastasis-associated protein, in endothelial cells inhibits tumor angiogenesis and growth. Angiogenesis. 2014;17:17–26.

  25. 25.

    Kriajevska M, Bronstein IB, Scott DJ, Tarabykina S, Fischer-Larsen M, Issinger O, et al. Metastasis-associated protein Mts1 (S100A4) inhibits CK2-mediated phosphorylation and self-assembly of the heavy chain of nonmuscle myosin. Biochim Biophys Acta. 2000;1498:252–63.

  26. 26.

    Dulyaninova NG, Malashkevich VN, Almo SC, Bresnick AR. Regulation of Myosin-IIA assembly and Mts1 binding by heavy chain phosphorylation. Biochemistry. 2005;44:6867–76.

  27. 27.

    Ford HL, Salim MM, Chakravarty R, Aluiddin V, Zain SB. Expression of Mts1, a metastasis-associated gene, increases motility but not invasion of a nonmetastatic mouse mammary adenocarcinoma cell line. Oncogene. 1995;11:2067–75.

  28. 28.

    Folkman J. Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg. 1972;175:409–16.

  29. 29.

    Meinert C, Kohse F, Böhme I, Gembardt F, Tetzner A, Wieland T, et al. Further intracellular proteins and signaling pathways regulated by angiotensin-(1-7) in human endothelial cells. Data Brief. 2017;10:354–63.

  30. 30.

    Li DQ, Ohshiro K, Reddy SD, Pakala SB, Lee MH, Zhang Y, et al. E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1. Proc Natl Acad Sci USA. 2009;13:17493–8.

  31. 31.

    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.

  32. 32.

    Höckel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 2001;93:266–76.

  33. 33.

    Semenza G. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol. 2002;64:993–8.

  34. 34.

    Jiang BH, Semenza GL, Bauer C, Marti HH. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol. 1996;271:1172–80.

  35. 35.

    Ghosh G, Subramanian IV, Adhikari N, Zhang X, Joshi HP, Basi D, et al. Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-α isoforms and promotes angiogenesis. J Clin Invest. 2010;120:4141–54.

  36. 36.

    Bartoszewska S, Kochan K, Piotrowski A, Kamysz W, Ochocka RJ, Collawn JF, et al. The hypoxia-inducible miR-429 regulates hypoxia-inducible factor-1α expression in human endothelial cells through a negative feedback loop. FASEB J. 2015;29:1467–79.

  37. 37.

    Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003;9:677–84.

  38. 38.

    Liu T, Zou W, Shi G, Xu J, Zhang F, Xiao J, et al. Hypoxia-induced MTA1 promotes MC3T3 osteoblast growth but suppresses MC3T3 osteoblast differentiation. Eur J Med Res. 2015;20:10.

Download references


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.

Author information

Correspondence to Hideya Endo.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Figure S1

Figure S2

Figure S3

Figure S4

Figure S5

Figure S6

Figure S7

Figure S8

Figure S9

Supplementary Figure Legends Marked up

Supplementary Figure Legends Clean

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7