Toll-like receptor 9 agonists promote cellular invasion by increasing matrix metalloproteinase activity

Toll-like receptor 9 (TLR9) recognizes microbial DNA. We show here that TLR9 protein is expressed in human breast cancer cells and clinical breast cancer samples. Stimulation of TLR9-expressing breast cancer cells with the TLR9 agonistic CpG oligonucleotides (1-10 mumol/L) dramatically increased the...

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Vydáno v:Molecular cancer research Ročník 4; číslo 7; s. 437
Hlavní autoři: Merrell, Melinda A, Ilvesaro, Joanna M, Lehtonen, Niko, Sorsa, Timo, Gehrs, Bradley, Rosenthal, Eben, Chen, Dongquan, Shackley, Brit, Harris, Kevin W, Selander, Katri S
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 01.07.2006
Témata:
Antibodies - pharmacology
Astrocytoma - enzymology
Astrocytoma - pathology
Breast Neoplasms - enzymology
Breast Neoplasms - pathology
Cell Line, Tumor
Collagenases - immunology
Collagenases - metabolism
CpG Islands
DNA-Binding Proteins - genetics
Glioblastoma - enzymology
Glioblastoma - pathology
Humans
Matrix Metalloproteinase 13
Matrix Metalloproteinase 8 - metabolism
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinases - metabolism
Neoplasm Invasiveness
Oligonucleotides - genetics
Oligonucleotides - pharmacology
Toll-Like Receptor 9 - agonists
Toll-Like Receptor 9 - biosynthesis
Toll-Like Receptor 9 - genetics
Toll-Like Receptor 9 - metabolism
ISSN:1541-7786
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Shrnutí:Toll-like receptor 9 (TLR9) recognizes microbial DNA. We show here that TLR9 protein is expressed in human breast cancer cells and clinical breast cancer samples. Stimulation of TLR9-expressing breast cancer cells with the TLR9 agonistic CpG oligonucleotides (1-10 mumol/L) dramatically increased their in vitro invasion in both Matrigel assays and three-dimensional collagen cultures. Similar effects on invasion were seen in TLR9-expressing astrocytoma and glioblastoma cells and in the immortalized human breast epithelial cell line MCF-10A. This effect was not, however, dependent on the CpG content of the TLR9 ligands because the non-CpG oligonucleotides induced invasion of TLR9-expressing cells. CpG or non-CpG oligonucleotide-induced invasion in MDA-MB-231 cells was blunted by chloroquine and they did not induce invasion of TLR9(-) breast cancer cells. Treatment of MDA-MB-231 cells with CpG or non-CpG oligonucleotides induced the formation of approximately 50-kDa gelatinolytic band in zymograms. This band and the increased invasion were abolished by a matrix metalloproteinase (MMP) inhibitor GM6001 but not by a serine proteinase inhibitor aprotinin. Furthermore, CpG oligonucleotide treatment decreased tissue inhibitor of metalloproteinase-3 expression and increased levels of active MMP-13 in TLR9-expressing but not TLR9(-) breast cancer cells without affecting MMP-8. Neutralizing anti-MMP-13 antibodies inhibited the CpG oligonucleotide-induced invasion. These findings suggest that infections may promote cancer progression through a novel TLR9-mediated mechanism. They also propose a new molecular target for cancer therapy, because TLR9 has not been associated with cancer invasiveness previously.
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ISSN:1541-7786
DOI:10.1158/1541-7786.mcr-06-0007