RT Journal Article
SR Electronic
T1 Src Induces <em>Urokinase Receptor</em> Gene Expression and Invasion/Intravasation via Activator Protein-1/p-c-Jun in Colorectal Cancer
JF Molecular Cancer Research
JO Mol Cancer Res
FD American Association for Cancer Research
SP 485
OP 496
DO 10.1158/1541-7786.MCR-06-0211
VO 5
IS 5
A1 Leupold, Jörg H.
A1 Asangani, Irfan
A1 Maurer, Gabriele D.
A1 Lengyel, Ernst
A1 Post, Stefan
A1 Allgayer, Heike
YR 2007
UL http://mcr.aacrjournals.org/content/5/5/485.abstract
AB 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 Ser73/63, and that this pathway is biologically relevant for colorectal cancer patients, suggesting therapeutic potential. (Mol Cancer Res 2007;5(5):485–96)