Modulation of CXC-motif chemokine receptor 7, but not 4, expression is related to migration of the human prostate cancer cell LNCaP: regulation by androgen and inflammatory stimuli.

Abstract

To elucidate the regulation, function of the chemokine CXC-motif ligand 12 (CXCL12) and its receptors (CXCR) 4 and 7 in prostate cancer tumor microenvironment. In-silico-analysis of expression in prostate cancer tissues. In-vitro comparison, testing of regulation in human prostate cancer cells LNCaP, DU145, and PC3. Dihydrotestosterone (DHT) treatments (0-10nM) were for 0-48h. The inflammatory agent Flagellin treatment (20ng/ml) was for 2h. Migration assays were performed for 24h using 10ng/ml CXCL12. Real-time PCR, western analysis, and migration assays were used to determine mRNA, protein, and functional changes, respectively. Malignant prostate cancer tissues exhibit higher CXCR4/7 mRNA ratio, and higher CXCR7 mRNA levels were detected in the androgen-responsive LNCaP cells. Putative androgen-responsive elements were identified in CXCR4, 7 gene, and exposure to DHT, flagellin increased CXCR4 mRNA but decreased CXCR7 mRNA levels in LNCaP cells. Androgen receptor siRNA significantly attenuated the effects of DHT on CXCR4, 7 mRNA in LNCaP cells. However, DHT and flagellin only decrease CXCR7 protein and additively increased migration of LNCaP cells towards CXCL12. Down regulation of CXCR7 protein by DHT and flagellin increased migration, supporting CXCR7 as decoy receptor counteracting CXCL12/CXCR4-mediated migration in prostate cancer cells.