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1.
Prostate ; 80(12): 938-949, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32542667

RESUMO

BACKGROUND: The clinical manifestation of benign prostatic hyperplasia (BPH) is causally linked to the inflammatory microenvironment and proliferation of epithelial and stromal cells in the prostate transitional zone. The CXC-chemokine interleukin-8 (IL-8) contributes to inflammation. We evaluated the expression of inflammatory cytokines in clinical specimens, primary cultures, and prostatic lineage cell lines. We investigated whether IL-8 via its receptor system (IL-8 axis) promotes BPH. METHODS: The messenger RNA and protein expression of chemokines, including components of the IL-8 axis, were measured in normal prostate (NP; n = 7) and BPH (n = 21), urine (n = 24) specimens, primary cultures, prostatic lineage epithelial cell lines (NHPrE1, BHPrE1, BPH-1), and normal prostate cells (RWPE-1). The functional role of the IL-8 axis in prostate epithelial cell growth was evaluated by CRISPR/Cas9 gene editing. The effect of a combination with two natural compounds, oleanolic acid (OA) and ursolic acid (UA), was evaluated on the expression of the IL-8 axis and epithelial cell growth. RESULTS: Among the 19 inflammatory chemokines and chemokine receptors we analyzed, levels of IL-8 and its receptors (CXCR1, CXCR2), as well as, of CXCR7, a receptor for CXCL12, were 5- to 25-fold elevated in BPH tissues when compared to NP tissues (P ≤ .001). Urinary IL-8 levels were threefold to sixfold elevated in BPH patients, but not in asymptomatic males and females with lower urinary tract symptoms (P ≤ .004). The expression of the IL-8 axis components was confined to the prostate luminal epithelial cells in both normal and BPH tissues. However, these components were elevated in BPH-1 and primary explant cultures as compared to RWPE-1, NHPrE1, and BHPrE1 cells. Knockout of CXCR7 reduced IL-8, and CXCR1 expression by 4- to 10-fold and caused greater than or equal to 50% growth inhibition in BPH-1 cells. Low-dose OA + UA combination synergistically inhibited the growth of BPH-1 and BPH primary cultures. In the combination, the drug reduction indices for UA and OA were 16.4 and 7852, respectively, demonstrating that the combination was effective in inhibiting BPH-1 growth at significantly reduced doses of UA or OA alone. CONCLUSION: The IL-8 axis is a promotor of BPH pathogenesis. Low-dose OA + UA combination inhibits BPH cell growth by inducing autophagy and reducing IL-8 axis expression in BPH-epithelial cells.


Assuntos
Interleucina-8/metabolismo , Próstata/metabolismo , Próstata/patologia , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Receptores CXCR/metabolismo , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Epitélio/patologia , Humanos , Interleucina-8/biossíntese , Interleucina-8/genética , Masculino , Ácido Oleanólico/farmacologia , Próstata/efeitos dos fármacos , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CXCR/biossíntese , Receptores CXCR/genética , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia
2.
Prostate ; 80(10): 731-741, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32356572

RESUMO

BACKGROUND: Male 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 uses LUTS and BPH interchangeably. More recently, LUTS were also linked to fibrogenic and inflammatory processes. We tested whether osteopontin (OPN), a proinflammatory and profibrotic molecule, is increased in symptomatic BPH. We also tested whether prostate epithelial and stromal cells secrete OPN in response to proinflammatory stimuli and identified downstream targets of OPN in prostate stromal cells. METHODS: Immunohistochemistry was performed on prostate sections obtained from the transition zone of patients who underwent surgery (Holmium laser enucleation of the prostate) to relieve LUTS (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 analysis. The ability of prostate cells to secrete osteopontin in response to IL-1ß and TGF-ß1 was determined in stromal (BHPrS-1) and epithelial (NHPrE-1 and BHPrE-1) cells by enzyme-linked immunosorbent assay. Quantitative polymerase chain reaction was used to measure gene expression changes in these cells in response to OPN. RESULTS: OPN immunostaining and protein levels were more abundant in S-BPH than I-BPH. Staining was distributed across all cell types with the highest levels in epithelial cells. Multiple OPN protein variants were identified in immortalized prostate stromal and epithelial cells. TGF-ß1 stimulated OPN secretion by NHPrE-1 cells and both IL-1ß and TGF-ß1 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. CONCLUSIONS: OPN is more abundant in prostates of men with S-BPH compared to men with I-BPH. OPN secretion is stimulated by proinflammatory cytokines, and OPN acts directly on stromal cells to drive the synthesis of proinflammatory mRNAs. Pharmacological manipulation of prostatic OPN may have the potential to reduce LUTS by inhibiting both inflammatory and fibrotic pathways.


Assuntos
Osteopontina/biossíntese , Hiperplasia Prostática/metabolismo , Quimiocinas CXC/biossíntese , Quimiocinas CXC/genética , Ciclo-Oxigenase 2/biossíntese , Ciclo-Oxigenase 2/genética , Humanos , Imuno-Histoquímica , Interleucina-6/biossíntese , Interleucina-6/genética , Masculino , Osteopontina/genética , Hiperplasia Prostática/genética , Hiperplasia Prostática/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Células Estromais/metabolismo , Células Estromais/patologia
3.
BMC Complement Med Ther ; 20(1): 150, 2020 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-32416730

RESUMO

BACKGROUND: Our previous study revealed the extract from the bark of an Amazonian tree Pao Pereira can suppress benign prostatic hyperplasia (BPH) in a rat model. Herein, we examined its inhibitory effects on human BPH cells and dissect its molecular mechanism. METHODS: We applied Pao extract to human BPH epithelial BPH-1 and prostate myofibroblast WPMY-1 cells. Cell viability, apoptosis and immunoblotting were performed, followed by gene expression profiling and gene set enrichment analysis (GSEA) to detect the differentially expressed genes and signaling pathway induced by Pao extract. Human ex vivo BPH explant organ culture was also used to examine the effects of Pao extract on human BPH tissues. RESULTS: Pao extract treatment inhibited viability and induced apoptosis in human BPH-1 and WPMY-1 cells. Gene expression profiling and the following validation indicated that the expression levels of pro-apoptotic genes (eg. PCDC4, CHOP and FBXO32) were induced by Pao extract in both two cell lines. GSEA further revealed that Pao extract treatment was negatively associated with the activation of NFκB signaling. Pao extract suppressed the transcriptional activity of NFκB and down-regulated its target genes involved in inflammation (CXCL5, CXCL6 and CXCL12) and extracellular matrix (ECM) remodeling (HAS2, TNC and MMP13) in both cultured cells and human ex vivo BPH explants. CONCLUSION: In both BPH epithelial and stromal cells, Pao extract induces apoptosis by upregulating the pro-apoptotic genes and inhibiting the inflammation-associated NFκB signaling via reducing phosphorylation of NFκB subunit RelA. Our data suggest that Pao extract may be a promising phytotherapeutic agent for BPH.


Assuntos
Apocynaceae/química , Apoptose/efeitos dos fármacos , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Hiperplasia Prostática/tratamento farmacológico , Apoptose/genética , Linhagem Celular , Humanos , Masculino , Casca de Planta/química , Hiperplasia Prostática/genética
4.
Nat Commun ; 11(1): 1987, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332823

RESUMO

Benign prostatic hyperplasia (BPH), a nonmalignant enlargement of the prostate, is among the most common diseases affecting aging men, but the underlying molecular features remain poorly understood, and therapeutic options are limited. Here we employ a comprehensive molecular investigation of BPH, including genomic, transcriptomic and epigenetic profiling. We find no evidence of neoplastic features in BPH: no evidence of driver genomic alterations, including low coding mutation rates, mutational signatures consistent with aging tissues, minimal copy number alterations, and no genomic rearrangements. At the epigenetic level, global hypermethylation is the dominant process. Integrating transcriptional and methylation signatures identifies two BPH subgroups with distinct clinical features and signaling pathways, validated in two independent cohorts. Finally, mTOR inhibitors emerge as a potential subtype-specific therapeutic option, and men exposed to mTOR inhibitors show a significant decrease in prostate size. We conclude that BPH consists of distinct molecular subgroups, with potential for subtype-specific precision therapy.


Assuntos
Próstata/patologia , Hiperplasia Prostática/genética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Agentes Urológicos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Biomarcadores/análise , Metilação de DNA , Epigênese Genética , Epigenômica , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/genética , Medicina de Precisão/métodos , Estudos Prospectivos , Próstata/diagnóstico por imagem , Próstata/efeitos dos fármacos , Hiperplasia Prostática/diagnóstico por imagem , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/patologia , RNA-Seq , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Agentes Urológicos/farmacologia , Sequenciamento Completo do Genoma
5.
Pharmacol Rep ; 72(1): 179-187, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32016843

RESUMO

BACKGROUND: Benign prostatic hyperplasia (BPH) is associated with obesity and prostatic inflammation. The present study investigated the participation of toll-like receptor 9 (TLR9) in obesity-induced BPH, focusing on metabolic impairments, damage-associated molecular patterns (DAMP) levels and prostatic oxidative stress generation. METHODS: C57BL/6 (WT) and TLR9 mutant male mice were fed with regular or high-fat diet for 12 weeks. Metabolic profile, functional protocols, reactive-oxygen species (ROS) generation, prostatic histological analysis and DAMP levels were analyzed. Western blotting for prostatic TLR9 signaling pathway was also performed. RESULTS: BPH in WT obese animals was characterized by increased prostate weight, smooth muscle hypercontractility and prostatic epithelial hyperplasia. Higher epididymal fat weight and prostatic ROS generation along with increased fasting glucose, triglyceride and circulating DAMP levels were also observed in WT obese group. Conversely, TLR9 mutant obese animals exhibited lower epididymal fat weight, fasting glucose and triglyceride levels associated with reduced prostate hypercontractility, prostatic ROS and circulating DAMP levels. However, TLR9 mutant obese mice were not protected from obesity-associated prostatic overgrowth and epithelial hyperplasia. Interestingly, TLR9 mutant lean mice exhibited augmented fasting glucose and prostatic ROS levels compared with WT lean mice. Despite increased prostatic expression of TLR9 in WT obese mice, no differences were seen in MyD88 expression between groups. CONCLUSION: Improved obesity-induced BPH-related prostatic smooth muscle hypercontractility in TLR9 obese mice may be associated with amelioration in the metabolic profile, ROS and DAMP generation. Therefore, TLR9 could be a valuable target to improve obesity-associated metabolic disorders and prostate smooth muscle hypercontractility in BPH.


Assuntos
Obesidade/complicações , Estresse Oxidativo/fisiologia , Hiperplasia Prostática/fisiopatologia , Receptor Toll-Like 9/genética , Alarminas/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Muscular/fisiologia , Músculo Liso/metabolismo , Hiperplasia Prostática/etiologia , Hiperplasia Prostática/genética , Espécies Reativas de Oxigênio/metabolismo
6.
Mol Cell Endocrinol ; 502: 110659, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31816356

RESUMO

Prostate cancer (PCa) is one of the most prevalent male tumours. Stanniocalcin-1 (STC1) is a glycoprotein and, although the role of STC1 in human cancer is poorly understood, it is suggested to be involved in the development and progression of different neoplasms. This study investigated the protein expression profile of STC1 in PCa and benign prostatic hyperplasia (BPH) samples and STC1 signalling during cell proliferation and cell death in vitro using cell lines. We found higher levels of STC1 in PCa when compared to BPH tissue and that STC1 inhibited forskolin stimulation of cAMP in PC-3 cells. A monoclonal antibody against STC1 was effective in reducing cell proliferation, in promoting cell cycle arrest, and in increasing apoptosis in the same cells. Since STC1 acts as a regulator of prostatic tissue signalling, we suggest that this protein is a novel candidate biomarker for prostate tumour clinical progression and a potential therapeutic target.


Assuntos
Biomarcadores Tumorais/metabolismo , Colforsina/farmacologia , Glicoproteínas/genética , Glicoproteínas/metabolismo , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/metabolismo , Apoptose , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Humanos , Masculino , Células PC-3 , Hiperplasia Prostática/genética , Neoplasias da Próstata/genética , Regulação para Cima
7.
Andrologia ; 52(1): e13386, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31733069

RESUMO

The miRNAs are dysregulated in BPH. Rape bee pollen (RBP) is used to improve benign prostatic hyperplasia (BPH). Whether RBP treats BPH by regulating the dysregulated miRNAs remains unclear. Here, we identified miRNAs regulated along with the improvement of BPH by RBP in posterior lobes of prostate in rats. Firstly, to screened miRNAs might relate to improvement of BPH by RBP, we compared differentially expressed miRNAs between BPH model group and RBP group by high-throughput sequencing. As a result, 10 known miRNAs and 17 novel miRNA were up-regulated in RBP group, and 6 known and 13 novel miRNAs were down-regulated. Secondly, among the known miRNAs, we identified those that might relate to BPH by RT-qPCR, while only rno-miR-184 was screened, so we compared it among normal control group, BPH model group and RBP group. The results showed that rno-miR-184 was significantly lower expressed in BPH group, but up-regulated along with the improvement of BPH by RBP. Moreover, expression level of rno-miR-184 was no difference between RBP group and normal control level. Therefore, we considered that RBP might improve BPH through regulating expression of miRNAs like rno-miR-184 in prostate in rats.


Assuntos
Apiterapia/métodos , Brassica rapa , MicroRNAs/metabolismo , Pólen , Hiperplasia Prostática/terapia , Animais , Humanos , Masculino , Próstata/efeitos dos fármacos , Próstata/patologia , Hiperplasia Prostática/genética , RNA-Seq , Ratos , Regulação para Cima/efeitos dos fármacos
8.
Sci Rep ; 9(1): 19703, 2019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31873149

RESUMO

Benign prostatic hyperplasia (BPH) is one of the most common diseases in the urinary system of elderly men. Pao extract is an herbal preparation of the bark of the Amazon rainforest tree Pao Pereira (Geissospermum vellosii), which was reported to inhibit prostate cancer cell proliferation. Herein we investigated the therapeutic potential of Pao extract against BPH development in a testosterone-induced BPH rat model. The administration of testosterone induced the prostate enlargement, compared with the sham operated group with vehicle treatment. The BPH/Pao group showed reduced prostate weight comparable with BPH/finasteride group. Notably, Pao treatment did not significantly reduce body weights and sperm number of rats, compared with the control group. Furthermore, Pao extract treatment reduced the proliferative index in prostate glands and testosterone-induced expression levels of AR, as well as androgen-associated proteins such as SRD5A1 and PSA. Moreover, Pao extract and its active component, flavopereirine, induced cytotoxicity on human prostate epithelial RWPE-1 cells in a dose- and time- dependent manner with G2/M arrest. Consistently, Pao extract and flavopereirine suppressed the expression levels of SRD5A1, AR and PSA, respectively. Together, these data demonstrated that Pao extract suppresses testosterone-induced BPH development through inhibiting AR activity and expression, and suggested that Pao extract may be a promising and relative safe agent for BPH.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Apocynaceae/química , Colestenona 5 alfa-Redutase/metabolismo , Extratos Vegetais/farmacologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/tratamento farmacológico , Animais , Carbolinas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Masculino , Extratos Vegetais/uso terapêutico , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Antígeno Prostático Específico/metabolismo , Hiperplasia Prostática/genética , Hiperplasia Prostática/patologia , Ratos Sprague-Dawley , Receptores Androgênicos/metabolismo , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Testosterona
9.
Biosci Rep ; 39(9)2019 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-31481527

RESUMO

Increasing evidence demonstrated that noncoding RNAs (lncRNA, miRNA) play important roles in the cancer development. LncRNA NEAT1 functions as an oncogene in many cancers. However, the roles of NEAT1 in prostate cancer (PCa) remain largely unknown. In the present study, we aim to explore the molecular mechanism of NEAT1 in the development of PCa. We detected the expression levels of NEAT1 in a total of 16 benign prostatic hyperplasia tissues (BPH), 30 matched adjacent healthy control (HC) tissues and 30 PCa tissues, as well as PCa cell lines PC-3, DU-145, LNCaP and normal prostate epithelial cell line RWPE-1. The results showed that NEAT1 was significantly up-regulated in PCa tissues and PCa cell lines. Knockdown of NEAT1 can largely inhibit DU-145 and PC-3 cell growth and invasion. Bioinformatics analysis predicted NEAT1 has the binding site of miR-98-5p which can bind to the 3'UTR of HMGA2. And the expression level of NEAT1 has a positive correlation with HMAG2, while negative correlation with miR-98-5p in PCa cells. In addition, luciference assay and RNA immunoprecipitation (RIP) assay confirmed that NEAT1 can function as a competing endogenous RNA (ceRNA) by sponging miR-98-5p to active HMGA2. Moreover, silencing of HMGA2 can decrease the proliferation ability of PCa cells. Taken together, NEAT1/miR-98-5p/HMGA2 pathway is involved in the development and progression of PCa. NEAT1 could be recommended as a prognostic biomarker and inhibition of NEAT1 expression may be a promising strategy for PCa therapy.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Proteína HMGA2/biossíntese , MicroRNAs/genética , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Idoso , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Proteína HMGA2/genética , Humanos , Masculino , Estadiamento de Neoplasias , Prognóstico , Hiperplasia Prostática/genética , Neoplasias da Próstata/patologia , Regulação para Cima/genética
10.
Andrologia ; 51(10): e13384, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31483058

RESUMO

Prostate cancer (PC) is considered as the fifth cause of cancer deaths worldwide. The exact etiopathogenesis is unclear; however, genetic predisposition, hormonal influencers, lifestyle and environmental factors act as major contributors. It has been found that several miRNAs may play a crucial role in cancer initiation and progression. Here, in this study, we evaluated the peripheral blood levels of miR-21, miR-141, miR-221 and miR-18a expression among 80 prostate cancer patients (50 localised and 30 metastatic) and 30 benign prostatic hyperplasia patients compared to 50 normal control subjects, using RT-PCR. Our results of analysis of miR-21, miR-141, miR-18a and miR-221 in the plasma of PC patients showed that miR-18a is a powerful discriminator of PC patients from healthy controls as it had the highest AUC (0.966; 95% CI, 0.937-1.000), while miR-221 provided better differentiation of metastatic from localised PC (sensitivity was 92.9% at 100% specificity), and when we combine miR-18a and miR-221 for differentiating patients with MPC, it will increase the sensitivity to 96.4% at a specificity of 100% (AUC, 0.997; 95% CI, 0.988-1.0) (p < .000). This current study recommends that analysis of these miRNAs might have clinical value in enhancing PSA testing.


Assuntos
Biomarcadores Tumorais/sangue , MicroRNA Circulante/sangue , MicroRNAs/sangue , Neoplasias da Próstata/diagnóstico , Adulto , Idoso , Diagnóstico Diferencial , Egito , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Hiperplasia Prostática/sangue , Hiperplasia Prostática/genética , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Curva ROC
11.
Clin Lab ; 65(8)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31414754

RESUMO

BACKGROUND: Prostate cancer is a common male cancer with poor prognosis, and to find molecular diagnostic markers for the early diagnosis of prostate cancer is urgently needed. The aim of this study is to investigate the diagnostic value of serum expression level of miR-494 for prostate cancer. METHODS: Ninety patients with prostate cancer and 90 patients with benign prostatic hyperplasia were enrolled in this study, and 90 healthy volunteers served as the control group. The serum of the participants was collected, and the expression level of miR-494 was measured by RT-PCR. Then the relationship between the expression of miR-494 and the clinical characteristics of the patients was analyzed. Moreover, the correlation between the expression of miR-494 and the Gleason score as well as serum level of prostate specific antigen (PSA) were analyzed. Finally, the diagnostic value of miR-494 for the early diagnosis of prostate cancer was analyzed by ROC curve. RESULTS: miR-494 was significantly increased in the prostatic hyperplasia group compared with the control group, and the level of miR-494 in the prostate cancer group was significantly higher than that in the prostatic hyperplasia group. The level of miR-494 in patients with prostate cancer was positively correlated with tumor size and tumor stage. Moreover, the level of miR-494 was positively correlated with the Gleason score (r = 0.3371, p = 0.0012) and serum level of PSA (r = 0.3485, p = 0.0008) in patients with prostate cancer. Finally, AUC of miR-494 was 0.8090 (95% confidence interval 0.7343 to 0.8837), suggesting that miR-494 is a sensitive biomarker for the diagnosis of prostate cancer. CONCLUSIONS: miR-494 was upregulated in the serum of the patients with prostate cancer and circulating miR-494 can be used as a biomarker for the early diagnosis of prostate cancer.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Hiperplasia Prostática/genética , Neoplasias da Próstata/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Hiperplasia Prostática/sangue , Hiperplasia Prostática/diagnóstico , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Curva ROC
12.
Anticancer Res ; 39(8): 4171-4177, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366502

RESUMO

BACKGROUND/AIM: Identification of prostatic stem cells in primary prostate tissue sections, organ cultures of prostate and cell lines requires a range of techniques that allows characterization of stem cells for their potential use in the treatment of patients. Isolated cells usually round-up and develop changes in shape, size and cellular characteristics. The aim of this study was to provide a range of methods for identifying prostatic stem cells and characterizing them with regard to ultrastructure, nuclear morphology, cytoplasmic organelles, and/or expression stem cell marker CD133. MATERIALS AND METHODS: Prostate biopsy and prostatectomy specimens were used for studying prostatic stem cells and their known marker CD133 in tissue sections by light and/or electron microscopy. Inverted capsule embedding was used to study archival metastatic prostate in pelvic nodes and Du145 cell line in a monolayer culture. RESULTS: Staining for CD133 positively identified stem cells that were found in benign prostatic hyperplasia, benign prostate, and prostate cancer cells. Paraffin embedded sections showed a single type of stem cells, whereas methylene blue-stained Epon sections showed both light and dark stem cells. Electron microscopy showed that both basal and stem cells were closely associated with the basement membrane (basal lamina). Stem cells had smooth plasma and nuclear membranes, a prominent nucleolus, small mitochondria, and few ribosomes. Du145 cells were separated by intercellular spaces in monolayer culture. CONCLUSION: The inverted capsule embedding method allowed the study of metastasized prostate cancer in pelvic lymph nodes. Our approach enabled the assessment of stem cells in tissue sections by light and electron microscopy.


Assuntos
Antígeno AC133/genética , Membrana Basal/ultraestrutura , Hiperplasia Prostática/genética , Neoplasias da Próstata/genética , Membrana Basal/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Microscopia Eletrônica , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/ultraestrutura , Próstata/metabolismo , Próstata/patologia , Próstata/ultraestrutura , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/ultraestrutura
13.
Mediators Inflamm ; 2019: 7894017, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360119

RESUMO

Investigations on prostate inflammation-related disorders, including acute and chronic prostatitis, chronic pelvic pain syndrome, benign prostate hyperplasia (BPH), and prostate cancer (PCa), are still ongoing to find new, accurate, and noninvasive biomarkers for a differential diagnosis of those pathological conditions sharing some common macroscopic features. Moreover, an ideal biomarker should be useful for risk assessment of prostate inflammation progression to more severe disorders, like BPH or PCa, as well as for monitoring of treatment response and prognosis establishment in carcinoma cases. Recent literature evidence highlighted that changes in the expression of transglutaminases, enzymes that catalyze transamidation reactions leading to posttranslational modifications of soluble proteins, occur in prostate inflammation-related disorders. This review focuses on the role specifically played by transglutaminases 4 (TG4) and 2 (TG2) and suggests that both isoenzymes hold a potential to be included in the list of candidates as novel diagnostic biomarkers for the above-cited prostate pathological conditions.


Assuntos
Biomarcadores Tumorais/metabolismo , Isoenzimas/metabolismo , Transglutaminases/metabolismo , Biomarcadores Tumorais/genética , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Humanos , Isoenzimas/genética , Masculino , Hiperplasia Prostática/genética , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Processamento de Proteína Pós-Traducional , Transglutaminases/genética
14.
Clin Lab ; 65(7)2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31307177

RESUMO

BACKGROUND: Prostate cancer (PC) is considered the fifth most common cancer causing death worldwide. Many studies have pointed to dysregulated microRNA (miRNA) expression in PC and their use in early detection and follow-up of the disease. In addition, the Prostate Health Index (PHI) is the FDA-approved blood test joining total, free, and -2proPSA having greater specificity than free and total PSA for assessment of PC. METHODS: In this study, we evaluated the plasma levels of miR-21and miR-221 expression using quantitative real-time polymerase chain reaction (qRT-PCR) among 100 prostate cancer patients (50 localized and 50 metastatic cases) and 50 benign prostatic hyperplasia patients in comparison to 50 normal control subjects, as well as assess-ed its diagnostic and prognostic value and its correlation with the Prostate Health Index (PHI). RESULTS: To our knowledge, we are the first study to join PHI with miRNAs in assessing PC diagnosis and progno-sis. Our results showed that adding miR-21 to PHI for detecting patients with LPC, increased the sensitivity to 95.5% at a specificity 100% (p < 0.0001). Additionally, combining miR-221 and PHI for differentiating patients with MPC, increased the sensitivity to 96.4% at a specificity 100% (p < 0.0001). CONCLUSIONS: The potentials of circulating miR-21, miR-221, and PHI serum level as biomarkers for PC have been established not only as diagnostic factors but also as prognostic markers.


Assuntos
Biomarcadores Tumorais/sangue , MicroRNAs/sangue , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico , Adulto , Idoso , Biomarcadores Tumorais/genética , Diagnóstico Diferencial , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Prognóstico , Hiperplasia Prostática/sangue , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/genética , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Curva ROC
15.
J Cell Physiol ; 234(11): 19942-19950, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31187492

RESUMO

Benign prostatic hyperplasia (BPH) is one of the most common causes of lower urinary tract symptoms (LUTS) in elderly man. However, the underlying molecular mechanisms of BPH have not been completely elucidated. We identified the key genes and pathways by using analysis of Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using edgeR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed for the DEGs by Database for Annotation, Visualization and Integrated Discovery (DAVID) database and ConsensusPathDB, respectively. Then, protein-protein interaction (PPI) networks were established by the Search Tool for the Retrieval of Interacting Genes (STRING) database and visualized by Cytoscape software. Finally, we identified 660 DEGs ultimately including 268 upregulated genes and 392 downregulated genes. GO analysis revealed that DEGs were mainly enriched in extracellular exosome, identical protein binding, mitochondrial adenosine triphosphate (ATP) synthesis coupled proton transport, extracelluar matrix, focal adhesion, cytosol, Golgi apparatus, cytoplasm, protein binding, and Golgi membrane. Focal adhesion pathway, FoxO signaling pathway, and autophagy pathway were selected. Ubiquitin-conjugating enzyme E2 C (UBE2C), serine/threonine kinase (AKT1), mitogen-activated protein kinase 1 (MAPK1), cyclin B1 (CCNB1), polo-like kinase 1 (PLK1) were filtrated as the hub genes according to the degree of connectivity from the PPI network. The five hub genes including UBE2C, AKT1, MAPK1, CCNB1, PLK1 may play key roles in the pathogenesis of benign prostatic hyperplasia (BPH). Focal adhesion pathway, FoxO signaling pathway, and autophagy pathway may be crucial for the progression of BPH.


Assuntos
Genes Neoplásicos , Hiperplasia Prostática/genética , Transdução de Sinais/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Genoma , Humanos , Masculino , Mapas de Interação de Proteínas/genética
16.
Prostate ; 79(11): 1199-1210, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31251827

RESUMO

BACKGROUND: With the popularity of serum prostate-specific antigen (PSA) screening, the number of newly diagnosed prostate cancer (PCa) patients is increasing. However, indolent or invasive PCa cannot be distinguished by PSA levels. Here, we mainly explored the role of heterogeneous nuclear ribonucleoprotein M (hnRNPM) in the invasiveness of PCa. METHODS: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis was used to detect the expressions of hnRNPM in PCa and benign prostate hyperplasia (BPH) tissues as well as in PCa cell lines. Immunohistochemistry was applied to detect the hnRNPM or Yin Yang 1 (YY1) expression in BPH, prostate adenocarcinoma (ADENO) and neuroendocrine prostate cancer (NEPC) tissues. After aberrant, the expression of hnRNPM in C4-2 and PC3 cells, the changes of cell migration and invasion were observed through wound-healing and transwell assays. We also predicted the transcription factor of hnRNPM through databases, then verified the association of hnRNPM and YY1 using chromatin immunoprecipitation (ChIP) and luciferase assays. RESULTS: The expression level of hnRNPM is gradually reduced in BPH, ADENO, and NEPC tissues and it is less expressed in more aggressive PCa cell lines. Overexpression of hnRNPM can significantly reduce Twist1 expression, which inhibits the migration and invasion of PCa cells in vitro. In PCa cells, overexpression of YY1 can promote epithelial-mesenchymal transition by reducing hnRNPM expression. Furthermore, this effect caused by overexpression of YY1 can be partially attenuated by simultaneous overexpression of hnRNPM. CONCLUSIONS: Our study demonstrates that hnRNPM negatively regulated PCa cell migration and invasion, and its expression can be transcriptionally inhibited by YY1. We speculated that hnRNPM may be a biomarker to assist in judging the aggressiveness of PCa.


Assuntos
Adenocarcinoma/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Ribonucleoproteínas Nucleares Heterogêneas Grupo M/metabolismo , Invasividade Neoplásica/genética , Neoplasias da Próstata/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo M/genética , Humanos , Masculino , Invasividade Neoplásica/patologia , Hiperplasia Prostática/genética , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Fator de Transcrição YY1/genética , Fator de Transcrição YY1/metabolismo
17.
Toxicol Appl Pharmacol ; 381: 114637, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31238046

RESUMO

Estrogens and androgens play critical roles during benign prostatic hyperplasia (BPH) development. Estrogen receptors (ERs), androgen receptor (AR) and aromatase, the key conversion enzyme of androgen to estrogen, are thought to be the effective targets for BPH treatment. Bakuchiol (Ba)-containing herb Psoralea corylifolia has been long-termed used for BPH patients in traditional Chinese medicine while the role and regulatory mechanism of Ba involved remain unclear. Human prostatic cell lines WPMY-1 and BPH-1 and oestrodial/testosterone-induced BPH rats were used as the in vitro and in vivo models. Ba significantly inhibited the proliferation of WPMY-1 and BPH-1 cells. In E2/T-induced BPH model, Ba treatment also significantly inhibited the enlargement of prostate, decreased PI values, reduced the thickness of periglanular smooth muscle layer, and down-regulated the expressions of PCNA and smooth muscle cell marker α-SMA, all of which were highly induced in BPH rats. Moreover, the basal and PGE2-induced expressions of aromatase were reduced in Ba-stimulated WPMY-1 cells, while the expression of ERß was highly increased in Ba-stimulated BPH-1 cells, both of which are consistent with the findings in Ba group in vivo. Ba induced ERE activity in BPH-1 cells as E2 did; however, silence of ERß not ERα, blocked Ba-induced ERE activity while E2 still exhibited the significant ERE activity, indicating the regulation of estrogen signaling by Ba is particularly via ERß. In conclusion, by down-regulation of stromal aromatase and up-regulation of epithelial ERß, Ba contributes to the balance of estrogen and androgen signaling and further inhibits BPH development.


Assuntos
Aromatase/metabolismo , Receptor beta de Estrogênio/metabolismo , Fenóis/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Animais , Aromatase/genética , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Estradiol/farmacologia , Receptor beta de Estrogênio/genética , Estrogênios/farmacologia , Humanos , Masculino , Camundongos , Fenóis/farmacologia , Hiperplasia Prostática/genética , Hiperplasia Prostática/metabolismo , Células RAW 264.7 , Ratos Wistar , Células THP-1 , Testosterona/farmacologia , Regulação para Cima/efeitos dos fármacos
18.
JCI Insight ; 52019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31094703

RESUMO

Benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptoms in men. Current treatments target prostate physiology rather than BPH pathophysiology and are only partially effective. Here, we applied next-generation sequencing to gain new insight into BPH. By RNAseq, we uncovered transcriptional heterogeneity among BPH cases, where a 65-gene BPH stromal signature correlated with symptom severity. Stromal signaling molecules BMP5 and CXCL13 were enriched in BPH while estrogen regulated pathways were depleted. Notably, BMP5 addition to cultured prostatic myofibroblasts altered their expression profile towards a BPH profile that included the BPH stromal signature. RNAseq also suggested an altered cellular milieu in BPH, which we verified by immunohistochemistry and single-cell RNAseq. In particular, BPH tissues exhibited enrichment of myofibroblast subsets, whilst depletion of neuroendocrine cells and an estrogen receptor (ESR1)-positive fibroblast cell type residing near epithelium. By whole-exome sequencing, we uncovered somatic single-nucleotide variants (SNVs) in BPH, of uncertain pathogenic significance but indicative of clonal cell expansions. Thus, genomic characterization of BPH has identified a clinically-relevant stromal signature and new candidate disease pathways (including a likely role for BMP5 signaling), and reveals BPH to be not merely a hyperplasia, but rather a fundamental re-landscaping of cell types.


Assuntos
Predisposição Genética para Doença/genética , Hiperplasia Prostática/genética , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Proteína Morfogenética Óssea 5/genética , Proteína Morfogenética Óssea 5/metabolismo , Exoma , Humanos , Masculino , Miofibroblastos , Células Neuroendócrinas , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores Estrogênicos , Índice de Gravidade de Doença , Transcriptoma
19.
PLoS One ; 14(4): e0215003, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30970027

RESUMO

Urine of prostate cancer (PCa) carries miRNAs originated from prostate cancer cells as a part of both nucleoprotein complexes and cell-secreted extracellular vesicles. The analysis of such miRNA-markers in urine can be a convenient option for PCa screening. The aims of this study were to reveal miRNA-markers of PCa in urine and design a robust and precise diagnostic test, based on miRNA expression analysis. The expression analysis of the 84 miRNAs in paired urine extracellular vesicles (EVs) and cell free urine supernatant samples from healthy donors, patients with benign and malignant prostate tumours was done using miRCURY LNA miRNA qPCR Panels (Exiqon, Denmark). Sets of miRNAs differentially expressed between the donor groups were found in urine EVs and urine supernatant. Diagnostically significant miRNAs were selected and algorithm of data analysis, based on expression data on 24-miRNA in urine and obtained using 17 analytical systems, was designed. The developed algorithm of data analysis describes a series of steps necessary to define cut-off values and sequentially analyze miRNA expression data according to the cut-offs to facilitate classification of subjects in case/control groups and allows to detect PCa patients with 97.5% accuracy.


Assuntos
MicroRNAs/genética , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/urina , Estudos de Casos e Controles , Interpretação Estatística de Dados , Vesículas Extracelulares/genética , Redes Reguladoras de Genes , Humanos , Masculino , MicroRNAs/urina , Pessoa de Meia-Idade , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/genética , Hiperplasia Prostática/urina , Neoplasias da Próstata/urina
20.
Sci Rep ; 9(1): 6077, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988330

RESUMO

Benign prostatic hyperplasia (BPH) results in a significant public health burden due to the morbidity caused by the disease and many of the available remedies. As much as 70% of men over 70 will develop BPH. Few studies have been conducted to discover the genetic determinants of BPH risk. Understanding the biological basis for this condition may provide necessary insight for development of novel pharmaceutical therapies or risk prediction. We have evaluated SNP-based heritability of BPH in two cohorts and conducted a genome-wide association study (GWAS) of BPH risk using 2,656 cases and 7,763 controls identified from the Electronic Medical Records and Genomics (eMERGE) network. SNP-based heritability estimates suggest that roughly 60% of the phenotypic variation in BPH is accounted for by genetic factors. We used logistic regression to model BPH risk as a function of principal components of ancestry, age, and imputed genotype data, with meta-analysis performed using METAL. The top result was on chromosome 22 in SYN3 at rs2710383 (p-value = 4.6 × 10-7; Odds Ratio = 0.69, 95% confidence interval = 0.55-0.83). Other suggestive signals were near genes GLGC, UNCA13, SORCS1 and between BTBD3 and SPTLC3. We also evaluated genetically-predicted gene expression in prostate tissue. The most significant result was with increasing predicted expression of ETV4 (chr17; p-value = 0.0015). Overexpression of this gene has been associated with poor prognosis in prostate cancer. In conclusion, although there were no genome-wide significant variants identified for BPH susceptibility, we present evidence supporting the heritability of this phenotype, have identified suggestive signals, and evaluated the association between BPH and genetically-predicted gene expression in prostate.


Assuntos
Predisposição Genética para Doença , Padrões de Herança , Hiperplasia Prostática/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Estudos de Casos e Controles , Registros Eletrônicos de Saúde/estatística & dados numéricos , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Próstata/patologia , Hiperplasia Prostática/epidemiologia , Hiperplasia Prostática/patologia
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