Introduction: Inflammation is implicated in the pathogenesis of benign prostatic hyperplasia (BPH) with advanced lower urinary tract symptoms (LUTS) and progression risk. Hippo-YAP pathway was demonstrated to regulate several crucial biological processes such as cell proliferation, fibrosis and organ regeneration. Considering our previous study demonstrated a significant cell proliferation and extracellular matrix deposition in inflammation-driven BPH, the current study was sought to investigate the role of hippo-Yes-associated protein 1 (YAP1) pathway in BPH model with inflammation and seek molecular clues to treat BPH.
Methods: Clinical specimens of transurethral resection of prostate were collected and divided into BPH with or without (n=10, each group) inflammation group based on histological observation. Masson staining, International Prostate Symptom Score (IPSS) and YAP1 immunohistochemistry were measured to analyze the correlation between YAP1 expression and fibrosis or LUTS. 24 rats were randomly allocated to normal control group (NC), testosterone-induced group (TI) and experimental autoimmune prostatitis group (EAP). The prostates of these rats were isolated to detect the YAP1 expression, inflammatory response, cell proliferation and apoptosis, fibrogenesis via quantitative PCR, western blot and immunohistochemistry examination. Such biochemical indicators were also determined in LPS-induced BPH epithelial cell line BPH-1 and stromal myofibroblast cell line WPMY-1. siRNA targeted YAP1 mRNA was applied to evaluate the curative effect of YAP1 suppression on BPH progression.
Results: BPH patients with inflammation performed elevated expression of YAP1. The average optical density of YAP1 were positively associated with the area ratio of collagen deposition and IPSS score. EAP rats performed enhanced nuclear localization of YAP1. Upregulated inflammatory mediators (COX-2, iNOS, IL-2), proliferation (PCNA, Ki67), fibrosis (Collagen I/III, TGF-ß/RhoA/ROCK1) and downregulated apoptosis (Bax/Bcl-2, cleaved caspase-3) were also observed in EAP model. Suppression of YAP1 using siRNA successfully reversed the processes of proliferation, anti-apoptosis and fibrosis in LPS-induced inflammation model of BPH-1 and WPMY-1 cells.
Conclusions: Inflammation-induced YAP1 activation are associated with severity of stromal fibrosis and LUTS performance. Nuclear YAP1 accumulation promoted cell proliferation, fibrosis but suppressed apoptosis. The induction of YAP1 expression initiated by inflammation is laying the groundwork for the depletion of YAP1 to the treatment of BPH.
Source of Funding: The National Natural Science Foundation of China (Grant number 81873625).
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