Estrogen and G protein-coupled estrogen receptor accelerate the progression of benign prostatic hyperplasia by inducing prostatic fibrosis

Abstract

Benign prostatic hyperplasia (BPH) is the most common and progressive urological disease in elderly men worldwide. Epidemiological studies have suggested that the speed of disease progression varies among individuals, while the pathophysiological mechanisms of accelerated clinical progression in some BPH patients remain to be elucidated. In this study, we defined patients with BPH as belonging to the accelerated progressive group (transurethral resection of the prostate [TURP] surgery at ≤50 years old), normal-speed progressive group (TURP surgery at ≥70 years old), or non-progressive group (age ≤50 years old without BPH-related surgery). We enrolled prostate specimens from the three groups of patients and compared these tissues to determine the histopathological characteristics and molecular mechanisms underlying BPH patients with accelerated progression. We found that the main histopathological characteristics of accelerated progressive BPH tissues were increased stromal components and prostatic fibrosis, which were accompanied by higher myofibroblast accumulation and collagen deposition. Mechanism dissection demonstrated that these accelerated progressive BPH tissues have higher expression of the CYP19 and G protein-coupled estrogen receptor (GPER) with higher estrogen biosynthesis. Estrogen functions via GPER/Gαi signaling to modulate the EGFR/ERK and HIF-1α/TGF-β1 signaling to increase prostatic stromal cell proliferation and prostatic stromal fibrosis. The increased stromal components and prostatic fibrosis may accelerate the clinical progression of BPH. Targeting this newly identified CYP19/estrogen/GPER/Gαi signaling axis may facilitate the development of novel personalized therapeutics to better suppress the progression of BPH.

YAP-mediated GPER signaling impedes proliferation and survival of prostate epithelium in benign prostatic hyperplasia

“… 21 , 34 And our newly reported work has revealed a pro-proliferation and pro-fibrosis role of GPER signaling via EGFR/ERK and HIF-1α/TGF-β1 signaling in prostatic stromal cell during BPH progression. 35 The observations that the expression of YAP was negatively correlated with the tissue estrogen content and GPER expression in epithelia of BPH specimens support a model of YAP deactivation by GPER in clinical samples. In this study, we confirmed that estrogen and G1 induced YAP phosphorylation and repressed their nuclear accumulation, diminishing the interaction between YAP and the transcription factor TEAD1.…”

Causal Associations Between Lifestyle Habits and Risk of Benign Prostatic Hyperplasia: A Two-Sample Mendelian Randomization Study

“…To explore the underlying mechanisms genetically linking exposure factors validated in this current study with BPH, we used IVW to estimate the association between the risk factors validated in the current study and other risk factors that have been reported to be associated with prostate enlargement, p < .05 was regarded as significant. Other risk factors for BPH noted in current studies include hypertension ( 31 ), obesity ( 32 ), dyslipidemia ( 33 ), and androgen and estrogen levels ( 34 ). The GWAS of these phenotypes are from the GIANT database ( 35 ), FinnGen Consortium ( 24 ), and NHGRI-EB Consortium ( 36 ).…”

“…To further investigate the mechanisms by which sleep levels influence BPH risk factors, we examined the relationship between sleep duration and several potential mediators, including hypertension ( 31 ), obesity ( 32 ), dyslipidemia ( 33 ), and androgens and estrogens ( 34 ), using the IVW method. Ultimately, a risk-causal relationship was found between sleep duration and testosterone levels and IVW (OR = 0.90, 95% CI = 0.84–0.97, p = .008); however, we did not observe a causal association between sleep duration and other potential risk factors for BPH ( Table 2 ).…”

Different Transcriptome Features of Peripheral Blood Mononuclear Cells in Non-Emphysematous Chronic Obstructive Pulmonary Disease

“…However, the role of NEU3 in COPD progression is unclear. Estrogen functions via GPER/Gαi signaling to modulate the EGFR/ERK and HIF-1α/TGF-β1 signaling to increase prostatic stromal cell proliferation and fibrosis [ 16 ]. NEU3 and GPER1 are associated with cell proliferation; however, the roles of these genes in COPD have not yet been determined.…”