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TAK1 is required for TGF-β1-mediated regulation of matrix metalloproteinase-9 and metastasis

Oncogene volume 27, pages 1198–1207 (2008)Cite this article

Abstract

Transforming growth factor-β 1 (TGF-β1) signaling in tumor cells has been implicated in tumor angiogenesis and metastasis by regulating matrix proteolysis. Although MMP-9/gelatinase-B is an important component of these TGF-β1 responses, the mechanism of its regulation is not well understood. Here, we present evidence that TGF-β-activated protein kinase 1 (TAK1) is critical for TGF-β regulation of MMP-9 and the metastatic potential of breast cancer cell line MDA-MB-231. We found that suppression of TAK1 signaling by dominant-negative (dn) TAK1 or RNA interference (siRNA) reduces expression of MMP-9 and tumor cell invasion, without growth inhibition in cell culture. The orthotopic xenograft studies in SCID mice showed that suppression of TAK1 signaling by dn-TAK1 reduces tumor growth and formation of lung metastases. Dn-TAK1 reduced the proliferation Ki-67 index and neovasculature of orthotopic xenografts. TAK1-mediated regulation of MMP-9 involves NF-κB signaling. Dn-TAK1 reduces NF-κB transcriptional response and inhibition of NF-κB reduces expression of MMP-9 and activity of the MMP-9 promoter reporter. Together, these findings suggest that TAK1 contributes to TGF-β1-mediated tumor angiogenesis and metastasis via a mechanism involving the TAK1–NF-κB–MMP-9 pathway.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

MAPK:

mitogen-activated protein kinase

MMP-9:

matrix metalloproteinase-9

TAK1:

TGF-β-activated protein kinase 1

TGF-β:

transforming growth factor-β

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Acknowledgements

We thank Hiroaki Sakurai and Jackie Bromberg for providing reagents; Heinz Baumann for critical reading of the manuscript; Mary M Vaughan and Karoly Toth for assistance with the immunohistochemistry and histopathology. This work was supported by PHS grant R01 CA95263 and USAMRMC grant DAMD17-02-01-0602 (to AVB) and in part by the Roswell Park Cancer Institute Cancer Center Support Grant CA 16056.

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  1. Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA

    A Safina, M-Q Ren, E Vandette & A V Bakin

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  1. A Safina
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  2. M-Q Ren
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  4. A V Bakin
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Correspondence to A V Bakin.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Safina, A., Ren, MQ., Vandette, E. et al. TAK1 is required for TGF-β1-mediated regulation of matrix metalloproteinase-9 and metastasis. Oncogene 27, 1198–1207 (2008). https://doi.org/10.1038/sj.onc.1210768

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