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


METHODS
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).


RESULTS
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.


CONCLUSIONS
The expression and function of PAR-1 in BPH stroma indicate PAR-1 may play important roles in BPH pathogenesis.
Wang
Wenbin
W
Department of Biochemistry, University of Washington, Seattle, Washington 98195-7350, USA.
Zhang
Xiaotun
X
Mize
Gregory J
GJ
Takayama
Thomas K
TK
D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D051523:Fibroblast Growth Factor 7 / Q000378:metabolism*; D006490:Hemostatics / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation; D011470:Prostatic Hyperplasia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D034741:RNA, Small Interfering; D044463:Receptor, PAR-1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism*; D013917:Thrombin / Q000494:pharmacology; D015854:Up-Regulation
C496453:FGF7 protein, human; D006490:Hemostatics; D009842:Oligopeptides; C462999:PAR-1-activating peptide; D034741:RNA, Small Interfering; D044463:Receptor, PAR-1; C508781:threonyl-phenylalanyl-leucyl-leucyl-arginyl-asparagine; D051523:Fibroblast Growth Factor 7; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013917:Thrombin