LncRNA DIO3OS regulated by TGF-β1 and resveratrol enhances epithelial mesenchymal transition of benign prostatic hyperplasia epithelial cells and proliferation of prostate stromal cells

Abstract Early studies suggested macrophages might play roles in inflammation-associated benign prostatic hyperplasia (BPH) development, yet the underlying mechanisms remain unclear. Here we first showed that CD68+ macrophages were identified in both epithelium and the stromal area of human BPH tissues. We then established an in vitro co-culture model with prostate epithelial and macrophage cell lines to study the potential impacts of infiltrating macrophages in the BPH development and found that co-culturing prostate epithelial cells with macrophages promoted migration of macrophages. In a three-dimensional culture system, the sphere diameter of BPH-1 prostate cells was significantly increased during coculture with THP-1 macrophage cells. Mechanism dissection suggested that expression levels of epithelial-mesenchymal transition (EMT) markers, such as N-cadherin, Snail, and TGF-β2, were increased, and administration of anti-TGF-β2 neutralizing antibody during co-culture suppressed the EMT and THP-1-mediated growth of BPH-1 cells, suggesting THP-1 might go through EMT to influence the BPH development and progression. Importantly, we found that modulation of androgen receptor (AR) in BPH-1 and mPrE cells significantly increased THP-1 and RAW264.7 cell migration, respectively, and enhanced expression levels of EMT markers, suggesting that AR in prostate epithelial cells might play a role in promoting macrophage-mediated EMT in prostate epithelial cells. Silencing AR function via an AR degradation enhancer, ASC-J9, decreased the macrophage migration to BPH-1 cells and suppressed EMT marker expression. Together, these results provide the first evidence to demonstrate that prostate epithelial AR function is important for macrophage-mediated EMT and proliferation of prostate epithelial cells, which represents a previously unrecognized role of AR in the cross-talk between macrophages and prostate epithelial cells. These results may provide new insights for a new therapeutic approach to battle BPH via targeting AR and AR-mediated inflammatory signaling pathways.

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Prostatic osteopontin expression is associated with symptomatic benign prostatic hyperplasia

10.1101/2019.12.23.887612 ◽

2019 ◽

Cited By ~ 1

Author(s):

Petra Popovics ◽

Wisam N. Awadallah ◽

Sarah Kohrt ◽

Thomas C. Case ◽

Nicole L. Miller ◽

...

Keyword(s):

Benign Prostatic Hyperplasia ◽

Epithelial Cells ◽

Stromal Cells ◽

Multispectral Imaging ◽

Imaging System ◽

Staining Intensity ◽

Prostatic Hyperplasia ◽

Low Grade ◽

Symptomatic Benign Prostatic Hyperplasia ◽

Tgf Β1

AbstractBackgroundMale lower urinary tract symptoms (LUTS) occur in more than half of men above 50 years of age. LUTS were traditionally attributed to benign prostatic hyperplasia (BPH) and therefore the clinical terminology often use LUTS and BPH interchangeably. More recently, LUTS were also linked to fibrogenic and inflammatory processes. We tested whether osteopontin (OPN), a pro-inflammatory and pro-fibrotic molecule, is increased in symptomatic BPH. We also tested whether prostate epithelial and stromal cells secrete OPN in response to pro-inflammatory stimuli and identified downstream targets of OPN in prostate stromal cells.MethodsImmunohistochemistry was performed on prostate sections obtained from the transition zone (TZ) of patients who underwent surgery (Holmium laser enucleation of the prostate) to relieve LUTS i.e. surgical BPH (S-BPH) or patients who underwent radical prostatectomy to remove low-grade prostate cancer (incidental BPH, I-BPH). Images of stained tissue sections were captured with a Nuance Multispectral Imaging system and histoscore, as a measure of OPN staining intensity, was determined with inForm software. OPN protein abundance was determined by Western blot. The ability of prostate cells to secrete osteopontin in response to IL-1β and TGF-β1 was determined in stromal (BHPrS-1) and epithelial (NHPrE-1 and BHPrE-1) cells by ELISA. qPCR was used to measure gene expression changes in these cells in response to OPN.ResultsOPN immunostaining (p=0.0107) and protein levels were more abundant in S-BPH than I-BPH. Staining was distributed across all cell types with highest levels in epithelial cells. Multiple OPN protein variants were identified in immortalized prostate stromal and epithelial cells. TGF-β1 stimulated OPN secretion by NHPrE-1 cells and both IL-1β and TGF-β1 stimulated OPN secretion by BHPrS-1 cells. Interestingly, recombinant OPN increased the mRNA expression of CXCL1, CXCL2, CXCL8, PTGS2 and IL6 in BHPrS-1, but not in epithelial cell lines.ConclusionsOPN is more abundant in prostates of men with S-BPH compared to men with I-BPH. OPN secretion is stimulated by pro-inflammatory cytokines, and OPN acts directly on stromal cells to drive the synthesis of pro-inflammatory mRNAs. Pharmacological manipulation of prostatic OPN may have the potential to reduce LUTS by inhibiting both inflammatory and fibrotic pathways.

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MicroRNA-340 Inhibits Epithelial-Mesenchymal Transition by Impairing ROCK-1-Dependent Wnt/β-Catenin Signaling Pathway in Epithelial Cells from Human Benign Prostatic Hyperplasia

Chinese Medical Journal ◽

10.4103/0366-6999.238145 ◽

2018 ◽

Vol 131 (16) ◽

pp. 2008-2012 ◽

Cited By ~ 3

Author(s):

Si-Yang Chen ◽

Yuan Du ◽

Jian Song

Keyword(s):

Benign Prostatic Hyperplasia ◽

Epithelial Cells ◽

Signaling Pathway ◽

Epithelial Mesenchymal Transition ◽

Prostatic Hyperplasia ◽

Mesenchymal Transition

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Evidence of TGF-β1 mediated epithelial-mesenchymal transition in immortalized benign prostatic hyperplasia cells

Molecular Membrane Biology ◽

10.3109/09687688.2014.894211 ◽

2014 ◽

Vol 31 (2-3) ◽

pp. 103-110 ◽

Cited By ~ 12

Author(s):

Shuai Hu ◽

Wei Yu ◽

Tian-Jing Lv ◽

Chawn-Shang Chang ◽

Xin Li ◽

...

Keyword(s):

Benign Prostatic Hyperplasia ◽

Epithelial Mesenchymal Transition ◽

Prostatic Hyperplasia ◽

Mesenchymal Transition ◽

Tgf Β1

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Faculty Opinions recommendation of A role for epithelial-mesenchymal transition in the etiology of benign prostatic hyperplasia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1156945.617010 ◽

2009 ◽

Author(s):

Giulio Gabbiani

Keyword(s):

Benign Prostatic Hyperplasia ◽

Epithelial Mesenchymal Transition ◽

Prostatic Hyperplasia ◽

Mesenchymal Transition

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The Crosstalk between Nrf2 and TGF-β1 in the Epithelial-Mesenchymal Transition of Pancreatic Duct Epithelial Cells

PLoS ONE ◽

10.1371/journal.pone.0132978 ◽

2015 ◽

Vol 10 (7) ◽

pp. e0132978 ◽

Cited By ~ 25

Author(s):

Sarah Arfmann-Knübel ◽

Birte Struck ◽

Geeske Genrich ◽

Ole Helm ◽

Bence Sipos ◽

...

Keyword(s):

Epithelial Cells ◽

Pancreatic Duct ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Tgf Β1

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Nitric oxide attenuates epithelial-mesenchymal transition in alveolar epithelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00475.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. L212-L221 ◽

Cited By ~ 54

Author(s):

Shilpa Vyas-Read ◽

Philip W. Shaul ◽

Ivan S. Yuhanna ◽

Brigham C. Willis

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Epithelial Cells ◽

Epithelial Mesenchymal Transition ◽

Alveolar Epithelial Cells ◽

No Production ◽

Mesenchymal Transition ◽

Alveolar Epithelial ◽

Oxide Synthase ◽

Tgf Β1

Patients with interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF) and bronchopulmonary dysplasia (BPD), suffer from lung fibrosis secondary to myofibroblast-mediated excessive ECM deposition and destruction of lung architecture. Transforming growth factor (TGF)-β1 induces epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AEC) to myofibroblasts both in vitro and in vivo. Inhaled nitric oxide (NO) attenuates ECM accumulation, enhances lung growth, and decreases alveolar myofibroblast number in experimental models. We therefore hypothesized that NO attenuates TGF-β1-induced EMT in cultured AEC. Studies of the capacity for endogenous NO production in AEC revealed that endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) are expressed and active in AEC. Total NOS activity was 1.3 pmol·mg protein−1·min−1 with 67% derived from eNOS. TGF-β1 (50 pM) suppressed eNOS expression by more than 60% and activity by 83% but did not affect iNOS expression or activity. Inhibition of endogenous NOS with l-NAME led to spontaneous EMT, manifested by increased α-smooth muscle actin (α-SMA) expression and a fibroblast-like morphology. Provision of exogenous NO to TGF-β1-treated AEC decreased stress fiber-associated α-SMA expression and decreased collagen I expression by 80%. NO-treated AEC also retained an epithelial morphology and expressed increased lamellar protein, E-cadherin, and pro-surfactant protein B compared with those treated with TGF-β alone. These findings indicate that NO serves a critical role in preserving an epithelial phenotype and in attenuating EMT in AEC. NO-mediated regulation of AEC fate may have important implications in the pathophysiology and treatment of diseases such as IPF and BPD.

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