MMP13 mediates cell cycle progression in melanocytes and melanoma cells: in vitro studies of migration and proliferation

Molecular Cancer

Research

Katarina Wolf¹  Peter Friedl¹  Anita Hufnagel²  Manfred Schartl²  Svenja Meierjohann²  Stefan Gaubatz²  Elisabeth Wende³  Markus A Kleinschmidt⁴ 

[1] Department of Cell Biology (283) NCMLS, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands;Department of Physiological Chemistry I, Biocenter, University of Wurzburg, 97074, Am Hubland, Wuerzburg, Germany;Department of Physiological Chemistry I, Biocenter, University of Wurzburg, 97074, Am Hubland, Wuerzburg, Germany;Institute for Medical Microbiology, Medical University of Hannover, Hannover, Germany;Physiological Chemistry, University Medical Center Utrecht, University of Utrecht, Netherlands;

关键词: Melanoma;    Melanoma Cell;    Human Melanoma Cell Line;    Lung Squamous Cell Carcinoma;    Starving Medium;   

DOI  :  10.1186/1476-4598-9-201

 received in 2010-01-29, accepted in 2010-07-28,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundMelanoma cells are usually characterized by a strong proliferative potential and efficient invasive migration. Among the multiple molecular changes that are recorded during progression of this disease, aberrant activation of receptor tyrosine kinases (RTK) is often observed. Activation of matrix metalloproteases goes along with RTK activation and usually enhances RTK-driven migration. The purpose of this study was to examine RTK-driven three-dimensional migration of melanocytes and the pro-tumorigenic role of matrix metalloproteases for melanocytes and melanoma cells.ResultsUsing experimental melanocyte dedifferentiation as a model for early melanomagenesis we show that an activated EGF receptor variant potentiates migration through three-dimensional fibrillar collagen. EGFR stimulation also resulted in a strong induction of matrix metalloproteases in a MAPK-dependent manner. However, neither MAPK nor MMP activity were required for migration, as the cells migrated in an entirely amoeboid mode. Instead, MMPs fulfilled a function in cell cycle regulation, as their inhibition resulted in strong growth inhibition of melanocytes. The same effect was observed in the human melanoma cell line A375 after stimulation with FCS. Using sh- and siRNA techniques, we could show that MMP13 is the protease responsible for this effect. Along with decreased proliferation, knockdown of MMP13 strongly enhanced pigmentation of melanocytes.ConclusionsOur data show for the first time that growth stimuli are mediated via MMP13 in melanocytes and melanoma, suggesting an autocrine MMP13-driven loop. Given that MMP13-specific inhibitors are already developed, these results support the evaluation of these inhibitors in the treatment of melanoma.

【 授权许可】

CC BY   
© Meierjohann et al; licensee BioMed Central Ltd. 2010