MTI-MMP regulates urothelial cell invasion via transcriptional regulation of Dickkopf-3

• Published in: British journal of cancer 2008-08, Vol.99 (4), p.663-669
• Main Authors: SAEB-PARSY, K, VEERAKUMARASIVAM, A, WALLARD, M. J, THORNE, N, KAWANO, Y, MURPHY, G, NEALL, D. E, MILLS, I. G, KELLY, J. D
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Medical sciences; Nephrology. Urinary tract diseases; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6604513

Membrane type-1 matrix metalloproteinase (MTI-MMP) is a zinc-binding endopeptidase, which plays a crucial role in tumour growth, invasion and metastasis. We have shown previously that MTI-MMP has higher expression levels in the human urothelial cell carcinoma (UCC) tissue. We show here that siRNA against MTI-MMP blocks invasion in UCC cell lines. Invasion is also blocked by broad-spectrum protease and MMP inhibitors including tissue inhibitor of metalloproteinase-1 and -2. Membrane type-1-MMP can also regulate transcription. We have used expression arrays to identify genes that are differentially transcribed when siRNA is used to suppress MTI-MMP expression. Upon MTI-MMP knockdown, Dickkopf-3 (DKK3) expression was highly upregulated. The stability of DKK3 mRNA was unaffected under these conditions, suggesting transcriptional regulation of DKK3 by MTI-MMP. Dickkopf-3 has been previously shown to inhibit invasion. We confirm that the overexpression of DKK3 Jeads to decreased invasive potential as well as delayed wound healing. We show for the first time that the effects of MTI-MMP on cell invasion are mediated in part through changes in DKK3 gene transcription.