TAK1 is required for TGF-beta 1-mediated regulation of matrix metalloproteinase-9 and metastasis

Oncogene. 2008 Feb 21;27(9):1198-207. doi: 10.1038/sj.onc.1210768. Epub 2007 Sep 10.


Transforming growth factor-beta 1 (TGF-beta1) 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-beta1 responses, the mechanism of its regulation is not well understood. Here, we present evidence that TGF-beta-activated protein kinase 1 (TAK1) is critical for TGF-beta 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-kappaB signaling. Dn-TAK1 reduces NF-kappaB transcriptional response and inhibition of NF-kappaB reduces expression of MMP-9 and activity of the MMP-9 promoter reporter. Together, these findings suggest that TAK1 contributes to TGF-beta1-mediated tumor angiogenesis and metastasis via a mechanism involving the TAK1-NF-kappaB-MMP-9 pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Female
  • Humans
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary*
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / physiology*
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / physiology
  • Mammary Neoplasms, Animal / enzymology*
  • Mammary Neoplasms, Animal / pathology
  • Matrix Metalloproteinase 9 / metabolism*
  • Matrix Metalloproteinase 9 / physiology
  • Mice
  • Mice, SCID
  • NF-kappa B / physiology
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / enzymology
  • Transforming Growth Factor beta1 / physiology*


  • NF-kappa B
  • Transforming Growth Factor beta1
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Matrix Metalloproteinase 9