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Transcriptional Regulation of Human Protease-Activated Receptor 1: A Role for the Early Growth Response-1 Protein in Prostate Cancer

Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem, Israel

Requests for reprints: Rachel Bar-Shavit, Department of Oncology, Hadassah-Hebrew University Hospital, P. O. Box 12000, Jerusalem 91120, Israel. Phone: 972-2-6777563; Fax: 972-2-6422794; E-mail: barshav{at}md.huji.ac.il.

Transcriptional regulation plays a central role in the molecular pathways underlying preferential cancer growth and metastasis. In the present study, we investigated the regulation of human protease-activated receptor 1 (hPar1) gene overexpression in the malignant androgen hormone-resistant phase. We found increased hPar1 RNA chain elongation and no change in message stability in cells with high levels of PAR1 expression, indicating that increased transcription is largely responsible for the overexpression of hPar1 in prostate tumor progression. Enforced expression of early growth response-1 (Egr-1) plasmid markedly enhanced luciferase activity driven by the hPar1 promoter. The neuroendocrine peptide bombesin significantly induced hPar1 expression and increased the ability of the cells to invade Matrigel, an effect abolished by expression of hPar1 small interfering RNA, showing the importance of hPAR1 in invasion. Bombesin also markedly enhanced Egr-1 binding to the hPar1 promoter in vivo and in vitro. These data suggest that bombesin enhances Egr-1 expression leading to increased hPar1 transcription, thereby increasing PAR1 expression and function. Immunohistostaining of prostate tissue biopsy specimens revealed a direct correlation between the degree of prostate cancer malignancy, PAR1 expression, and EGR-1 expression. Altogether, we show that transcriptional regulation of hPar1 in the aggressive hormone-resistant prostate cancer stage is controlled in part by the transcription factor Egr-1 and may play a central role in invasiveness, an important indicator of malignancy. [Cancer Res 2007;67(20):9835–43]