Up-regulation of FGF7 induced Intra-vesical Prostatic Protrusion of Benign Prostatic Hyperplasia via the ERK1/2 signaling pathway

Introduction: Intra-vesical Prostatic Protrusion (IPP) has been reported to be associated with bladder outlet obstruction (BOO) and is the main cause of LUTS during the development of Benign Prostatic Hyperplasia (BPH). However, the molecular mechanism of IPP is still unclear.

Methods: Clinical data analysis was performed to detect the association of IPP and long-term complications in patients with BPH. To explore the molecular mechanism of IPP formation, we performed RNA sequencing on prostate tissues (IPP or not) Stromal cells obtained from IPP-derived primary cultures. Cell proliferation was evaluated by CCK-8 assay. Multiple proteins in the signaling pathway were assessed using western blot.

Results: Firstly, we confirmed that IPP is a prognostic factor for long-term complications in patients with BPH. Then, Fibroblast Growth Factor 7 (FGF7) was up-regulated in IPP tissues compared to normal prostate tissues through RNA sequencing. We observed that FGF7 was up-regulated in both IPP tissues and IPP primary stromal cells through IHC, Western-blot and qRT-PCR. Meanwhile, FGF7 expression is significantly up-regulated in high IPP grade prostate tissues. Down-regulation of FGF7 in IPP-derived stromal cells led to impairment of proliferation and migration of the prostate epithelial cells via co-culture experiments. Additionally, FGF7 induced the epithelial-mesenchymal transition (EMT) process through binding to FGFR2. RNA sequencing analysis also revealed the activation of MAPK/ERK1/2 signaling pathway. Moreover, down-regulation of MAPK/ERK1/2 by specific inhibitor impacted effects of FGF7 stimulation in vitro.

Conclusions: Our data revealed a novel amplification effect, namely stromal cells derived FGF7 promotes epithelial cell proliferation as well as stromal cell phenotype which eventually induced IPP formation. And targeting FGF7 significantly reduced epithelial to stromal transition, also providing a potential therapeutic target for BPH progression.