Protease-activated receptor-1 upregulates fibroblast growth factor 7 in stroma of benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is characterized by abnormal epithelial and stromal proliferation causing urinary obstruction. Prostate growth is regulated by a variety of growth factors secreted from the stroma, including fibroblast growth factor 7 (FGF-7), a potent epithelial-specific growth factor which is increased in hyperplastic prostate. However, the mediator(s) of FGF-7 over-expression is unclear. Protease-activated receptor-1 (PAR-1) is a G-protein coupled receptor known to induce multiple biological processes, but its effect on BPH pathogenesis is mostly unknown. The aim of this study was to investigate the role of PAR-1 as a mediator of BPH development.

PAR-1 expression was investigated in BPH and normal prostate tissues by immunohistochemistry. Prostate stromal cells were isolated from BPH specimens, cultured and immunohistochemically characterized. Cultured stromal cells were stimulated with PAR-1 agonists, and extracellular-signal regulated kinase (ERK1/2) activation and cell proliferation were examined. PAR-1 mediated FGF-7 production by cultured stromal cells was assessed by RT-PCR and immunoassays, and verified by small interfering RNA (siRNA).

PAR-1 expression was increased in BPH stroma. In stromal cells isolated from BPH tissues, PAR-1 agonists activated ERK1/2 in a time- and concentration-dependent manner and with resultant enhanced cell proliferation. Pertussis toxin-sensitive G protein/(betagamma-subunits)-phosphatidylinositol 3-kinase and protein kinase C pathways were involved in ERK1/2 phosphorylation. PAR-1 activation strikingly induced FGF-7 production from cultured stromal cells mediated predominantly via ERK1/2 signaling pathway, and PAR-1 siRNA decreased the elicited FGF-7 upregulation.

The expression and function of PAR-1 in BPH stroma indicate PAR-1 may play important roles in BPH pathogenesis.