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Extracellular Matrix Metalloproteinase Inducer Up-regulates the Urokinase-Type Plasminogen Activator System Promoting Tumor Cell Invasion

¹ Institut National de la Sante et de la Recherche Medicale U716; ² Université Paris 7- IUH; ³ Laboratory of Pharmacology, AP-HP, Hôpital Saint-Louis; ⁴ Fondation A. de Rothschild, Department of Ophthalmology, Paris, France; and ⁵ Laboratoire de Recherche sur la Croissance Cellulaire la Reparation et la Régéneration Tissulaire, Centre National de la Recherche Scientifique UMR 7149, Université Paris XII, Créteil, France

Requests for reprints: Samia Mourah, Laboratoire de Pharmacologie and Institut National de la Sante et de la Recherche Medicale U716, Hôpital Saint-Louis, 27, rue Juliette Dodu, 75010 Paris, France. Phone: 33-1-42-49-48-85; Fax: 33-1-42-49-49-89; E-mail: samia.mourah{at}sls.aphp.fr.

Extracellular matrix metalloproteinase inducer (EMMPRIN) is a membrane glycoprotein overexpressed in many cancer tissues and is known for its ability to stimulate MMP expression. In this work, we show that EMMPRIN is also a regulator of the urokinase-type plasminogen activation (uPA) system of serine proteases, thus participating to the increase of the overall proteolytic function of the cancer cells. Enhanced EMMPRIN expression in a tumorigenic breast epithelial cell line NS2T2A increased the levels of uPA, uPA receptor, and the uPA inhibitor plasminogen activator inhibitor-1 (PAI-1), as measured by quantitative reverse transcription-PCR, Western blot, and plasminogen-casein zymography. This response was down-regulated by either EMMPRIN small interfering RNA or a blocking antibody to EMMPRIN. EMMPRIN-containing purified membrane fraction from Chinese hamster ovary cells when added exogenously to NS2T2A cells induced a similar activation of the uPA/PAI-1 system. Additionally, overexpression of EMMPRIN in NS2T2A cells increased uPA levels in cocultured endothelial cells, showing a paracrine regulation loop involving a tumor-stroma interaction. EMMPRIN-expressing cells also exhibited enhanced invasive potential in vitro, and the use of amiloride (uPA inhibitor) and marimastat (MMP inhibitor) showed that the two proteolytic systems reduced alone and in combination the invasive potential mediated through EMMPRIN. These data show a novel regulatory pathway for uPA activity and suggest that EMMPRIN is involved in uPA dysregulation observed in cancer. [Cancer Res 2007;67(1):9–15]

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