The effect of oxytocin on cell proliferation in the human prostate is modulated by gonadal steroids: implications for benign prostatic hyperplasia and carcinoma of the prostate

Benign prostatic hyperplasia (BPH) is a quite common illness but its etiology and mechanism remain unclear. Neural epidermal growth factor-like like 2 (NELL2) plays multifunctional roles in neural cell growth and is strongly linked to the urinary tract disease. Current study aims to determine the expression, functional activities and underlying mechanism of NELL2 in BPH. Human prostate cell lines and tissues from normal human and BPH patients were utilized. Immunohistochemical staining, immunofluorescent staining, RT-PCR and Western-blotting were performed. We further generated cell models with NELL2 silenced or overexpressed. Subsequently, proliferation, cycle, and apoptosis of prostate cells were determined by CCK-8 assay and flow cytometry analysis. The epithelial-mesenchymal transition (EMT) and fibrosis process were also analyzed. Our study revealed that NELL2 was upregulated in BPH samples and localized in the stroma and the epithelium compartments of human prostate tissues. NELL2 deficiency induced a mitochondrial-dependent cell apoptosis, and inhibited cell proliferation via phosphorylating ERK1/2 activation. Additionally, suppression of ERK1/2 with U0126 incubation could significantly reverse NELL2 deficiency triggered cell apoptosis. Consistently, overexpression of NELL2 promoted cell proliferation and inhibited cell apoptosis. However, NELL2 interference was observed no effect on EMT and fibrosis process. Our novel data demonstrated that upregulation of NELL2 in the enlarged prostate could contribute to the development of BPH through enhancing cell proliferation and inhibited a mitochondrial-dependent cell apoptosis via the ERK pathway. The NELL2-ERK system might represent an important target to facilitate the development of future therapeutic approaches in BPH.

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Effects of shRNA‑mediated silencing of PDE5A3 on intracellular cGMP and free Ca2+ levels and human prostate smooth muscle cell proliferation from benign prostatic hyperplasia

Experimental and Therapeutic Medicine ◽

10.3892/etm.2021.9753 ◽

2021 ◽

Vol 21 (4) ◽

Author(s):

Zheng Xu ◽

Yuzheng Ge ◽

Ke Jiang ◽

Luwei Xu ◽

Jiageng Zhu ◽

...

Keyword(s):

Cell Proliferation ◽

Smooth Muscle ◽

Benign Prostatic Hyperplasia ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Prostatic Hyperplasia ◽

Smooth Muscle Cell Proliferation ◽

Human Prostate ◽

Intracellular Cgmp

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Localization of angiotensin-converting enzyme in the human prostate: pathological expression in benign prostatic hyperplasia

The Journal of Pathology ◽

10.1002/path.999 ◽

2001 ◽

Vol 195 (5) ◽

pp. 571-579 ◽

Cited By ~ 29

Author(s):

Labrini Nassis ◽

Albert G. Frauman ◽

Mitsuru Ohishi ◽

Jialong Zhuo ◽

David J. Casley ◽

...

Keyword(s):

Benign Prostatic Hyperplasia ◽

Angiotensin Converting Enzyme ◽

Prostatic Hyperplasia ◽

Human Prostate ◽

Converting Enzyme

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High-Fat Diet Induced Gut Microbiota Alterations Associating With Ghrelin/Jak2/Stat3 Up-Regulation to Promote Benign Prostatic Hyperplasia Development

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.615928 ◽

2021 ◽

Vol 9 ◽

Author(s):

Meng Gu ◽

Chong Liu ◽

TianYe Yang ◽

Ming Zhan ◽

Zhikang Cai ◽

...

Keyword(s):

Cell Proliferation ◽

Benign Prostatic Hyperplasia ◽

Gut Microbiota ◽

High Fat Diet ◽

Prostatic Hyperplasia ◽

Prostate Tissue ◽

High Fat ◽

Ghrelin Receptor

The role of high-fat diet (HFD) induced gut microbiota alteration and Ghrelin as well as their correlation in benign prostatic hyperplasia (BPH) were explored in our study. The gut microbiota was analyzed by 16s rRNA sequencing. Ghrelin levels in serum, along with Ghrelin and Ghrelin receptor in prostate tissue of mice and patients with BPH were measured. The effect of Ghrelin on cell proliferation, apoptosis, and induction of BPH in mice was explored. Our results indicated that BPH mice have the highest ratio of Firmicutes and Bacteroidetes induced by HFD, as well as Ghrelin level in serum and prostate tissue was significantly increased compared with control. Elevated Ghrelin content in the serum and prostate tissue of BPH patients was also observed. Ghrelin promotes cell proliferation while inhibiting cell apoptosis of prostate cells. The effect of Ghrelin on enlargement of the prostate was found almost equivalent to that of testosterone propionate (TP) which may be attenuated by Ghrelin receptor antagonist YIL-781. Ghrelin could up-regulate Jak2/pJak2/Stat3/pStat3 expression in vitro and in vivo. Our results suggested that Gut microbiota may associate with Ghrelin which plays an important role in activation of Jak2/Stat3 in BPH development. Gut microbiota and Ghrelin might be pathogenic factors for BPH and could be used as a target for mediation.

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Ghrelin Aggravates Prostate Enlargement in Rats with Testosterone-Induced Benign Prostatic Hyperplasia, Stromal Cell Proliferation, and Smooth Muscle Contraction in Human Prostate Tissues

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/4748312 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 1

Author(s):

Xiaolong Wang ◽

Yiming Wang ◽

Christian Gratzke ◽

Christian Sterr ◽

Qingfeng Yu ◽

...

Keyword(s):

Smooth Muscle ◽

Benign Prostatic Hyperplasia ◽

Muscle Contraction ◽

Stromal Cell ◽

Molecular Mechanisms ◽

Smooth Muscle Contraction ◽

Prostatic Hyperplasia ◽

Human Prostate ◽

Mrna Levels ◽

Prostate Enlargement

Epidemiologic studies revealed a context between lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) and metabolic syndrome. However, molecular mechanisms underlying this relationship are largely unknown. Prostate enlargement and increased prostate smooth muscle tone are important factors in the pathophysiology of LUTS suggestive of BPH. In the present study, we studied effects of the metabolic hormone ghrelin on prostate enlargement in rats with experimentally induced BPH, growth of cultured stromal cells from human prostate (WPMY-1), and smooth muscle contraction of human prostate tissues. Ghrelin (20 nmol/kg daily, p.o., 2 weeks) increased prostate size in rats with testosterone-induced BPH. Microarray identified 114 ghrelin-upregulated genes (2-fold or more) in these prostates, with possible roles in growth, smooth muscle contraction, or metabolism. 12 genes were selected for further analyses. In human prostate tissues, mRNA levels of 11 of them correlated positively with ghrelin receptor (GHSR) expression, but only two with the degree of BPH. Accordingly, no correlation was evident between GHSR expression level and BPH in human prostate tissues. In WPMY-1 cells, the GHRS agonist MK0677 upregulated 11 of the selected genes. MK0677 induced proliferation of WPMY-1 cells, shown by EdU assay, colony formation, proliferation markers, flow cytometry, and viability. In myographic measurements, GHSR agonists enhanced contractions of human prostate strips. Together, ghrelin may aggravate prostate enlargement, stromal cell growth, and prostate smooth muscle contraction in BPH. Ghrelin may deteriorate urethral obstruction independently from BPH, qualifying the ghrelin system as an attractive new target to be tested for LUTS treatment in BPH.

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