Human antigen R is positively associated with malignant aggressiveness via upregulation of cell proliferation, migration, and vascular endothelial growth factors and cyclooxygenase-2 in prostate cancer

Limited information is available on the pathologic significance of human antigen R (HuR) in prostate cancer (PCa). The main aim of this study was to clarify the relationship between HuR expression and malignant aggressiveness, outcome, and expression of cancer-related molecules in PCa. In vitro proliferation, colony formation, and migration assays were performed on LNCaP and PC-3 cells. HuR expression was knocked down (KD) using small interfering RNA. The relationships between HuR expression and the expression of vascular endothelial growth factors (VEGFs), cyclooxygenase (COX)-2, and heme oxygenase (HO)-1 were investigated in PCa cell lines using Western blotting. On KD of HuR, cell proliferation and migration were suppressed in both LNCaP and PC-3 cells, whereas expression of VEGF-A to -D and COX-2 was suppressed in PC-3 but not in LNCaP cells. In addition, expression of these cancer-related factors was analyzed in 182 hormone-naive PCa and 23 castration resistant prostate cancer (CRPC) human tissues in vivo. Cytoplasmic (C)-HuR expression was significantly higher in CRPC > hormone-naive PCa > nontumoral cells. C-HuR expression was positively associated with Gleason score, T stage, and metastasis, and it was considered to be a useful predictor of biochemical recurrence after radical prostatectomy. C-HuR expression was correlated with COX-2 expression in hormone-naive PCa, and with the expression of VEGF-A, VEGF-C, and COX-2 in CRPC tissues. Our results demonstrated that HuR plays important roles in determining malignant aggressiveness and outcome in PCa, especially in androgen independent PCa cells, via the regulation of cell proliferation, migration, and expression of VEGF-A, -C, and COX-2.