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J. Biol. Chem., Vol. 279, Issue 30, 31769-31779, July 23, 2004

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Roles of Stem Cell Factor/c-Kit and Effects of Glivec®/STI571 in Human Uveal Melanoma Cell Tumorigenesis^*

Gaëlle Lefevre, Anne-Lise Glotin¶, Armelle Calipel¶, Frédéric Mouriaux||, Thi Tran**, Zoulika Kherrouche, Claude-Alain Maurage, Christian Auclair¶¶, and Frédéric Mascarelli||||

From the INSERM U598, Institut Biomédical des Cordeliers, 75006 Paris, France, ^||Service d'Ophtalmologie, CHU-Caen, 14000 Caen, France, ^**AB Science, 75008 Paris, France, UMR 8117, CNRS/Institut de Biologie, 59000 Lille, France, Service d'Anatomie Pathologique et Service Commun de Morphologie Cellulaire, Faculté de Médecine, 59000 Lille, France, and ^¶¶UMR 8113, CNRS/ENS, 94235 Cachan, France

The B-Raf^V599E-mediated constitutive activation of ERK1/2 is involved in establishing the transformed phenotype of some uveal melanoma cells (Calipel, A., Lefevre, G., Pouponnot, C., Mouriaux, F., Eychene, A., and Mascarelli, F. (2003) J. Biol. Chem. 278, 42409–42418). We have shown that stem cell factor (SCF) is involved in the proliferation of normal uveal melanocytes and that c-Kit is expressed in 75% of primary uveal melanomas. This suggests that the acquisition of autonomous growth during melanoma progression may involve the SCF/c-Kit axis. We used six human uveal melanoma tumor-derived cell lines and normal uveal melanocytes to characterize the SCF/c-Kit system and to assess its specific role in transformation. We investigated the possible roles of activating mutations in c-KIT, the overexpression of this gene, and ligand-dependent c-Kit overactivation in uveal melanoma cell tumorigenesis. Four cell lines (92.1, SP6.5, Mel270, and TP31) expressed both SCF and c-Kit, and none harbored the c-KIT mutations in exons 9, 11, 13, and 17 that have been shown to induce SCF-independent c-Kit activation. Melanoma cell proliferation was strongly inhibited by small interfering RNA-mediated depletion of c-Kit in these cells, despite the presence of ^V599EB-Raf in SP6.5 and TP31 cells. We characterized the signaling pathways involved in SCF/c-Kit-mediated cell growth and survival in normal and tumoral melanocytes and found that constitutive ERK1/2 activation played a key role in both the SCF/c-Kit autocrine loop and the gain of function of ^V599EB-Raf for melanoma cell proliferation and transformation. We also provide the first evidence that Glivec®/STI571, a c-Kit tyrosine kinase inhibitor, could be used to treat uveal melanomas.

Received for publication, April 8, 2004 , and in revised form, May 13, 2004.

^* This work was supported by grants from the Association pour la Recherche sur le Cancer (to F. M.); the Ligue Nationale Contre le Cancer, Comité de Paris (to F. M. and G. L.); and the Association Française des Amblyopes Unilatéraux (to F. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by fellowships from the French Ministère de la Recherche.

^¶ These authors contributed equally to this work.

^|||| Corresponding author: Institut Biomédical des Cordeliers, INSERM U598, 15 Rue de l'Ecole de Médecine, 75006, Paris, France. E-mail: fmascar{at}infobiogen.fr.

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