期刊
ONCOGENE
卷 27, 期 9, 页码 1198-1207出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1210768
关键词
angiogenesis; invasion; metastasis; MMP-9; TAK1; TGF-beta
资金
- NCI NIH HHS [CA 16056, R01 CA95263, R01 CA095263, P30 CA016056] Funding Source: Medline
Transforming growth factor-beta 1 (TGF-beta 1) 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-b1 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. QJ; Dn-TAK1 reduced the proliferation Ki-67 index and neovasculature of orthotopic xenografts. TAK1-mediated regulation of MMP-9 involves NF-kappa B signaling. Dn-TAK1 reduces NF-kappa B transcriptional response and inhibition of NF-kappa B reduces expression of MMP-9 and activity of the MMP-9 promoter reporter. Together, these findings suggest that TAK1 contributes to TGF-beta 1-mediated tumor angiogenesis and metastasis via a mechanism involving the TAK1-NF-kappa B-MMP-9 pathway.
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