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J. Biol. Chem., Vol. 282, Issue 21, 15490-15497, May 25, 2007

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Activating Transcription Factor-1-mediated Hepatocyte Growth Factor-induced Down-regulation of Thrombospondin-1 Expression Leads to Thyroid Cancer Cell Invasion^*

Christelle Ghoneim¹, Mahdhia Soula-Rothhut, Charlotte Blanchevoye, Laurent Martiny, Frank Antonicelli^¶, and Bernard Rothhut²

From the Unité Matrice Extracellulaire et Régulations Cellulaires, Laboratory of Biochemistry and the ^¶Department of Dermatology, Université de Reims Champagne Ardenne (URCA), CNRS, 51687 Reims, France

Hepatocyte growth factor (HGF) plays a major role in the pathogenesis of a variety of human epithelial tumors including papillary carcinoma of the thyroid. Previous reports demonstrated that HGF, acting through the Met receptor, repressed thrombospondin-1 (TSP-1) expression. To study the mechanisms by which HGF down-regulated TSP-1 expression, we transiently transfected a panel of deleted human TSP-1 promoter reporter plasmids into papillary thyroid carcinoma cells. We identified a region between –1210 and –1123 bp relative to the transcription start site that is responsive to HGF treatment and harbors a cAMP-responsive element (CRE) at position –1199 (TGACGTCC). Overexpression of various members of the CRE-binding protein family identified activating transcription factor-1 (ATF-1) as the transcription factor responsible for HGF-induced repression of TSP-1 promoter activity. This inhibition was associated with a concomitant increase in the abundance of nuclear ATF-1 protein. Gel shift and antibody supershift studies indicated that ATF-1 was involved in DNA binding to the TSP-1-CRE site. Finally, we utilized small hairpin RNA to target ATF-1 and showed that these small interfering RNA constructs significantly inhibited ATF-1 expression at both the RNA and the protein level. ATF-1 knockdown prevented HGF-induced down-regulation of TSP-1 promoter activity and protein expression and also reduced HGF-dependent tumor cell invasion. Taken together, our results indicate that HGF-induced down-regulation of TSP-1 expression is mediated by the interaction of ATF-1 with the CRE binding site in the TSP-1 promoter and that this transcription factor plays a crucial role for tumor invasiveness in papillary carcinoma of the thyroid triggered by HGF.

Received for publication, November 15, 2006 , and in revised form, April 2, 2007.

^* This work was supported by CNRS, by Association pour la Recherche sur le Cancer Contract 7734 and by Ligue Nationale contre le Cancer, Comitéde la Marne. 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.

¹ Supported by a predoctoral fellowship from the Région Champagne-Ardenne.

² To whom correspondence should be addressed: Laboratory of Biochemistry, URCA, CNRS UMR 6198, Moulin de la Housse, 51687 Reims, France. Tel.: 33-3-26-91-33-48; Fax: 33-3-26-91-83-66; E-mail: bernard.rothhut{at}univ-reims.fr.

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