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Signaling and Regulation

Src Induces Urokinase Receptor Gene Expression and Invasion/Intravasation via Activator Protein-1/p-c-Jun in Colorectal Cancer

¹ Department Experimental Surgery Mannheim Faculty, University of Heidelberg, and Molecular Oncology of Solid Tumors Unit, Deutsches Krebsforschungszentrum; ² Department Surgery, Mannheim Faculty,University Heidelberg, Heidelberg, Germany; and ³ Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Chicago, Chicago, Illinois

Requests for reprints: Heike Allgayer, Department of Experimental Surgery and Molecular Oncology of Solid Tumors, German Cancer Research Center Heidelberg, Mannheim Faculty, Ruprecht Karls University Heidelberg, Theodor Kutzer Ufer 1-3, 68135 Mannheim, Germany. Phone: 49-621-383-2226; Fax: 49-621-383-3839. E-mail: heike.allgayer{at}chir.ma.uni-heidelberg.de

The urokinase receptor [urokinase plasminogen activator receptor (u-PAR)] promotes invasion and metastasis and is associated with poor patient survival. Recently, it was shown that Src induces u-PAR gene expression via Sp1 bound to the u-PAR promoter region –152/–135. However, u-PAR is regulated by diverse promoter motifs, among them being an essential activator protein-1 (AP-1) motif at –190/–171. Moreover, an in vivo relevance of Src-induced transcriptional regulators of u-PAR–mediated invasion, in particular intravasation, and a relevance in resected patient tumors have not sufficiently been shown. The present study was conducted (a) to investigate if, in particular, AP-1–related transcriptional mediators are required for Src-induced u-PAR–gene expression, (b) to show in vivo relevance of AP-1–mediated Src-induced u-PAR gene expression for invasion/intravasation and for resected tissues from colorectal cancer patients. Src stimulation of the u-PAR promoter deleted for AP-1 region –190/–171 was reduced as compared with the wild-type promoter in cultured colon cancer cells. In gelshifts/chromatin immunoprecipitation, Src-transfected SW480 cells showed an increase of phospho–c-Jun, in addition to JunD and Fra-1, bound to region –190/–171. Src-transfected cells showed a significant increase in c-Jun phosphorylated at Ser⁷³ and also Ser⁶³, which was paralleled by increased phospho–c-jun-NH₂-kinase. Significant decreases of invasion/in vivo intravasation (chorionallantoic membrane model) were observed in Src-overexpressing cells treated with Src inhibitors, u-PAR–small interfering RNA, and dominant negative c-Jun (TAM67). In resected tissues of 20 colorectal cancer patients, a significant correlation between Src activity, AP-1 complexes bound to u-PAR region –190/–171, and advanced pN stage were observed. These data suggest that Src-induced u-PAR gene expression and invasion/intravasation in vivo is also mediated via AP-1 region –190/–171, especially bound with c-Jun phosphorylated at Ser^73/63, and that this pathway is biologically relevant for colorectal cancer patients, suggesting therapeutic potential. (Mol Cancer Res 2007;5(5):485–96)