Matrix metalloproteinase-13 is regulated by toll-like receptor-9 in colorectal cancer cells and mediates cellular migration

Rath,Timo; Stöckle,Julia; Roderfeld,Martin; Tschuschner,Annette; Graf,Jürgen; Roeb,Elke

doi:10.3892/ol.2011.276

Matrix metalloproteinase-13 is regulated by toll-like receptor-9 in colorectal cancer cells and mediates cellular migration

Authors:
- Timo Rath
- Julia Stöckle
- Martin Roderfeld
- Annette Tschuschner
- Jürgen Graf
- Elke Roeb
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Affiliations: Department of Gastroenterology, Medical Clinic II, Justus Liebig University, D-35392 Giessen, Germany, Faculty of Medicine, Philipps-University Marburg, Marburg, Germany
Published online on: March 21, 2011 https://doi.org/10.3892/ol.2011.276
Pages: 483-488

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Abstract

Matrix metalloproteinases (MMPs) are associated with cancer cell invasion and metastasis, and are currently the most prominent proteases associated with tumorigenesis. In particular, abundant expression of MMP-13 in colorectal cancer (CRC) is correlated with poor survival and the existence of distant metastasis. As suggested by recent in vitro studies, MMP-13 expression is regulated in a toll-like receptor (TLR)-9-dependent manner. In this study, we quantified the expression of MMP-13, TLR-9 and second messengers of the TLR signal transduction in CRC cells compared to colonic fibroblasts by RT-PCR. Furthermore, the effects of a selective TLR-9 stimulation on the expression of MMP-13 in CRC cells and colonic fibroblasts were analyzed. MMP-13 and TLR-9 as well as associated second messengers were simultaneously up-regulated in LS174 and SW620 cells compared to fibroblasts. Selective TLR-9 agonism with CpG oligonucleotides led to a significant increase in MMP-13 gene expression after 12 h of incubation in LS174 cells and after 12 and 24 h in SW620 cells, but not when using GpC oligonucleotides as a control substance. By contrast, MMP-13 gene expression remained unchanged in colonic fibroblasts following treatment with CpG or GpC oligonucleotides. The effects of selective MMP-13 inhibition on cellular migration were analyzed in Boyden chamber experiments. In the presence of 10 and 20 µM of the specific MMP-13 inhibitor, CL-82198, migration of the LS174 cells was significantly reduced by 55 and 52%, respectively, compared to untreated cells. In conclusion, the results of this study provide evidence of the TLR-9-dependent regulation of MMP-13 in CRC cells, but not in colonic fibroblasts. Since the specific inhibition of MMP-13 significantly reduces the migration of LS174 cells, selective MMP-13 inhibition may be a promising therapeutic strategy in CRC.

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