Epithelial-to-mesenchymal transition and estrogen receptor α mediated epithelial dedifferentiation mark the development of benign prostatic hyperplasia

Shao, Rui; Shi, Jiandang; Liu, Haitao; Shi, Xiaoyu; Du, Xiaoling; Klocker, Helmut; Lee, Chung; Zhu, Yan; Zhang, Ju

doi:10.1002/pros.22814

Cited by 43 publications

(35 citation statements)

References 35 publications

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“…Its incidence gradually increases with age; more than two-thirds of men aged over 50 have histological evidence of BPH and about half of the male population older than 50 years suffers from BPH-associated LUTS symptoms, such as urgency, frequency and retention2526. Aging and the presence of androgens are necessary for the development of BPH, but its pathogenesis still remains unresolved23. Accumulating evidence suggests that intraprostatic inflammation and inflammatory factors play a critical role in the pathogenesis of BPH and in the aggravation of its clinical symptoms27282930.…”

Section: Discussionmentioning

confidence: 99%

LPS/TLR4 Signaling Enhances TGF-β Response Through Downregulating BAMBI During Prostatic Hyperplasia

Chen

et al. 2016

Sci Rep

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Compelling evidence suggests that benign prostatic hyperplasia (BPH) development involves accumulation of mesenchymal-like cells derived from the prostatic epithelium by epithelial-mesenchymal transition (EMT). Transforming growth factor (TGF)-β induces EMT phenotypes with low E-cadherin and high vimentin expression in prostatic epithelial cells. Here we report that LPS/TLR4 signalling induces down-regulation of the bone morphogenic protein and activin membrane-bound inhibitor (BAMBI), which enhances TGF-β signalling in the EMT process during prostatic hyperplasia. Additionally, we found that the mean TLR4 staining score was significantly higher in BPH tissues with inflammation compared with BPH tissues without inflammation (5.13 ± 1.21 and 2.96 ± 0.73, respectively; P < 0.001). Moreover, patients with inflammatory infiltrate were more likely to have a higher age (P = 0.020), BMI (P = 0.026), prostate volume (P = 0.024), total IPSS score (P = 0.009) and IPSS-S (P < 0.001). Pearson’s correlation coefficient and multiple regression analyses demonstrated that TLR4 mRNA expression level was significantly positively associated with age, BMI, serum PSA levels, urgency and nocturia subscores of IPSS in the inflammatory group. These findings provide new insights into the TLR4-amplified EMT process and the association between TLR4 levels and storage LUTS, suggesting chronic inflammation as vital to the pathogenesis of BPH.

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Section: Discussionmentioning

confidence: 99%

LPS/TLR4 Signaling Enhances TGF-β Response Through Downregulating BAMBI During Prostatic Hyperplasia

Chen

et al. 2016

Sci Rep

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“…This study sheds light on the paracrine roles of GHRH in prostatic inflammation and demonstrates that GHRH stimulates the growth of BPH-1 and primary prostate epithelial spheres and that GHRH antagonists reduce prostate volume in an experimental model of prostatic inflammation. in vitro inflammation model (25)(26)(27). However, little is known about the exact molecular mechanism how the chronic prostatitis/EMT/BPH transition may occur.…”

Section: Significancementioning

confidence: 99%

Antagonists of growth hormone-releasing hormone inhibit proliferation induced by inflammation in prostatic epithelial cells

Popovics

Salgueiro

Kovacs

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The etiology of benign prostatic hyperplasia (BPH) is multifactorial, and chronic inflammation plays a pivotal role in its pathogenesis. Growth hormone-releasing hormone (GHRH) is a hypothalamic neuropeptide that has been shown to act as paracrine/autocrine factor in various malignancies including prostate cancer. GHRH and its receptors are expressed in experimental models of BPH, in which antagonists of GHRH suppressed the levels of proinflammatory cytokines and altered the expression of genes related to epithelial-to-mesenchymal transition (EMT). We investigated the effects of GHRH antagonist on prostatic enlargement induced by inflammation. Autoimmune prostatitis in Balb/C mice was induced by a homogenate of reproductive tissues of male rats. During the 8-wk induction of chronic prostatitis, we detected a progressive increase in prostatic volume reaching 92% at week 8 compared with control (P < 0.001). Daily treatment for 1 mo with GHRH antagonist MIA-690 caused a 30% reduction in prostate volume (P < 0.05). Conditioned medium derived from macrophages increased the average volume of spheres by 82.7% (P < 0.001) and elevated the expression of mRNA for N-cadherin, Snail, and GHRH. GHRH antagonist reduced the average volume of spheres stimulated by inflammation by 75.5% (P < 0.05), and TGF-β2 by 91.8% (P < 0.01). The proliferation of primary epithelial cells stimulated by IL-17A or TGF-β2 was also inhibited by 124.1% and 69.9%, respectively. GHRH stimulated the growth of BPH-1 and primary prostate spheres. This study provides evidence that GHRH plays important roles in prostatic inflammation and EMT and suggests the merit of further investigation to elucidate the effects of GHRH antagonists in prostatitis and BPH. chronic prostatic inflammation | neuropeptide | prostatic hyperplasia | targeted therapy | experimental autoimmune prostatitis

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“…Interestingly, the expression of ERa (ESR1) dramatically increases in the epithelium and is much lower than normal levels in the stroma (Nicholson et al 2013). The estrogen antagonist raloxifene has been shown to inhibit BPH epithelial growth and may be a major mediator of epithelialto-mesenchymal transition (EMT) in BPH tissue (Yang et al 2010, Shao et al 2014. The inductive abilities of the BPH stroma are thought to be embryonic signals that induce normal epithelial structures.…”

Section: Cancermentioning

confidence: 99%

Influence of stromal–epithelial interactions on androgen action

Nieto

Rider

Cramer

2014

Endocrine-Related Cancer

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Androgen receptor (AR) signaling is vital to the development and function of the prostate and is a key pathway in prostate cancer. AR is differentially expressed in the stroma and epithelium, with both paracrine and autocrine control throughout the prostate. Stromalepithelial interactions within the prostate are commonly dependent on AR signaling and expression. Alterations in these pathways can promote tumorigenesis. AR is also expressed in normal and malignant mammary tissues. Emerging data indicate a role for AR in certain subtypes of breast cancer that has the potential to be exploited therapeutically. The aim of this review is to highlight the importance of these interactions in normal development and tumorigenesis, with a focus on the prostate and breast.

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Epithelial-to-mesenchymal transition and estrogen receptor α mediated epithelial dedifferentiation mark the development of benign prostatic hyperplasia

Abstract: Epithelial and mesenchymal phenotype switching is an important mechanism in the etiology of BPH. ERα mediated enhanced estrogenic effect is a crucial inductive factor of epithelial dedifferentiation giving rise to activation of an EMT program in prostate epithelium.

Cited by 43 publications

References 35 publications

LPS/TLR4 Signaling Enhances TGF-β Response Through Downregulating BAMBI During Prostatic Hyperplasia

LPS/TLR4 Signaling Enhances TGF-β Response Through Downregulating BAMBI During Prostatic Hyperplasia

Antagonists of growth hormone-releasing hormone inhibit proliferation induced by inflammation in prostatic epithelial cells

Influence of stromal–epithelial interactions on androgen action

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