scholarly journals New Insights into the Role of Polybromo-1 in Prostate Cancer

2019 ◽  
Vol 20 (12) ◽  
pp. 2852 ◽  
Author(s):  
Sara T. S. Mota ◽  
Lara Vecchi ◽  
Mariana A. P. Zóia ◽  
Fabrícia M. Oliveira ◽  
Douglas A. Alves ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Expression Patterns ◽  
Specific Antigen ◽  
Tissue Microarrays ◽  
Mrna Levels ◽  
Castration Resistant ◽  
Chromatin Remodeling Complex ◽  
Prostatic Cell

The human protein Polybromo-1 (PBMR1/BAF180) is a component of the SWI/SNF chromatin-remodeling complex that has been reported to be deregulated in tumors. However, its role in prostate cancer (PCa) is largely unknown. In this study, we described the PBRM1 transcriptional levels and the protein expression/localization in tissues of PCa patients and in prostatic cell lines. Increased PBRM1 mRNA levels were found in PCa samples, when compared to benign disease, and were correlated with higher Gleason score. We also verified that only the nuclear localization of PBRM1 protein is correlated with a more aggressive disease and high Prostate-Specific Antigen (PSA) levels in tissue microarrays. Intriguing expression patterns of mRNA and protein were identified in the cell lines. Although PBRM1 protein was restricted to the nuclei, in tumor cell lines in non-neoplastic cells, it was also present in vesicular-like structures that were dispersed within the cytoplasm. We knocked-down PBRM1 in the castration-resistant PCa (CRPC) cell line PC-3 and we verified that PBRM1 promotes the expression of several markers of aggressiveness, including EpCAM, TGF-β, and N-Cadherin. Therefore, our data supported the hypothesis that PBRM1 displays a pivotal role in the promotion and maintenance of the malignant behavior of PCa, especially in CRPC.

scholarly journals Role of a novel race-related tumor suppressor microRNA located in frequently deleted chromosomal locus 8p21 in prostate cancer progression

2019 ◽  
Vol 40 (5) ◽  
pp. 633-642 ◽  
Author(s):  
Divya Bhagirath ◽  
Thao Ly Yang ◽  
Z Laura Tabatabai ◽  
Varahram Shahryari ◽  
Shahana Majid ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Cancer Progression ◽  
Specific Antigen ◽  
Tumor Grade ◽  
Clinical Samples ◽  
Mesenchymal Transition ◽  
Microrna Genes

Abstract The prostate cancer (PCa) genome is characterized by deletions of chromosome 8p21–22 region that increase significantly with tumor grade and are associated with poor prognosis. We proposed and validated a novel, paradigm-shifting hypothesis that this region is associated with a set of microRNA genes—miR-3622, miR-3622b, miR-383—that are lost in PCa and play important mechanistic roles in PCa progression and metastasis. Extending our hypothesis, in this study, we evaluated the role of a microRNA gene located in chromosome 8p—miR-4288—by employing clinical samples and cell lines. Our data suggests that (i) miR-4288 is widely downregulated in primary prostate tumors and cell lines; (ii) miR-4288 expression is lost in metastatic castration-resistant PCa; (ii) miR-4288 downregulation is race-related PCa alteration that is prevalent in Caucasian patients and not in African Americans; (iii) in Caucasians, miR-4288 was found to be associated with increasing tumor grade and high serum prostate-specific antigen, suggesting that miR-4288 downregulation/loss may be associated with tumor progression specifically in Caucasians; (iv) miR-4288 possess significant potential as a molecular biomarker to predict aggressiveness/metastasis; and (v) miR-4288 is anti-proliferative, is anti-invasive and inhibits epithelial-to-mesenchymal transition; and (vi) miR-4288 directly represses expression of metastasis/invasion-associated genes MMP16 and ROCK1. Thus, the present study demonstrates a tumor suppressor role for a novel miRNA located with a frequently lost region in PCa, strengthening our hypothesis that this locus is causally related to PCa disease progression via loss of microRNA genes. Our study suggests that miR-4288 may be a novel biomarker and therapeutic target, particularly in Caucasians.

MiR-1271-5p: An AR-modulatory microRNA with a distinct role in prostate cancer progression, through SND1 and MORF4L1 interaction.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16562-e16562
Author(s):  
Foteini Kalofonou ◽  
Damien Leach ◽  
Mark Hamilton ◽  
Sean Eric Mcguire ◽  
Claire Fletcher ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Target Genes ◽  
Prostatic Tissue ◽  
Screening Methods ◽  
Mrna Levels ◽  
Resistant Disease ◽  
Castrate Resistant

e16562 Background: Current screening methodologies for prostate cancer (PCa) are relatively insensitive and there is a need for new treatments for castrate resistant disease. MicroRNAs (miRs) are considered to be master regulators of the genome. We have investigated the role of miRs in modulating androgen receptor function and their potential as treatments of PCa. We report that the AR-modulatory miR-1271-5p also targets SND1 and MORF4L1 and may have a role in PCa progression and screening. Methods: AGO2-PAR-CLIP analysis was performed to ascertain miR-1271-5p target genes in human PCa cell lines. MiR-1271-5p levels were manipulated in cell lines by transfection with miR mimic and or antisense inhibitor. SND1 and MORF4L1 were confirmed as targets by real-time qPCR and western blotting. The functional role of miR-1271-5p and its target genes was assessed by SRB growth assays . Immunohistochemical detection of SND1 and MORF4L1 expression was studied in a cohort of 63 PCa patients and compared with normal controls. Results: MORF4L1 mRNA levels were significantly reduced with the use of miR-1271-5p mimic in 22RV1 cells (p = 0.001), while SND1 mRNA levels were significantly decreased with the use of miR-1271-5p inhibitor in C42 cells (p = 0.0014). Targeting SND1 or MORF4L1, in combination with miR inhibition, significantly reduced C42 (p = 0.0003) and 22RV1 (p = 0.0014) cell growth. MORF4L1 expression was higher in patients with Gleason score (GS) 4+3 relative to those with GS 3+4 and in PCa tissue, as compared with normal prostatic tissue, but did not reach significance. SND1 immunostaining was significantly higher in patients with GS 4+3 or GS 3+4 PCa, compared with normal prostatic tissue (p = 0.0211, p = 0.0007 respectively). SND1 staining was significantly higher in patients with GS 4+3, compared to GS 3+4 (p = 0.0431) or GS 3+3 (p = 0.0251). Conclusions: MiR-1271-5p is an AR-modulatory microRNA, which shows great potential as a biomarker and therapeutic target in PCa. The interaction of miR-1271-5p with its target genes SND1 and MORF4L1 could provide the basis for therapeutic advance in screening and in the treatment of castrate resistant PCa.

scholarly journals Proximity Ligation Assay as a Tool for Antibody Validation in Human Tissues

2020 ◽  
Vol 68 (7) ◽  
pp. 515-529 ◽  
Author(s):  
Cecilia Lindskog ◽  
Max Backman ◽  
Agata Zieba ◽  
Anna Asplund ◽  
Mathias Uhlén ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cell Lines ◽  
Expression Patterns ◽  
Basic Research ◽  
Tissue Microarrays ◽  
Cancer Diagnostics ◽  
Proximity Ligation Assay ◽  
Mrna Levels ◽  
Proximity Ligation ◽  
Antibody Validation

Immunohistochemistry (IHC) is the accepted standard for spatial analysis of protein expression in tissues. IHC is widely used for cancer diagnostics and in basic research. The development of new antibodies to proteins with unknown expression patterns has created a demand for thorough validation. We have applied resources from the Human Protein Atlas project and the Antibody Portal at National Cancer Institute to generate protein expression data for 12 proteins across 39 cancer cell lines and 37 normal human tissue types. The outcome of IHC on consecutive sections from both cell and tissue microarrays using two independent antibodies for each protein was compared with in situ proximity ligation (isPLA), where binding by both antibodies is required to generate detection signals. Semi-quantitative scores from IHC and isPLA were compared with expression of the corresponding 12 transcripts across all cell lines and tissue types. Our results show a more consistent correlation between mRNA levels and isPLA as compared to IHC. The main benefits of isPLA include increased detection specificity and decreased unspecific staining compared to IHC. We conclude that implementing isPLA as a complement to IHC for analysis of protein expression and in antibody validation pipelines can lead to more accurate localization of proteins in tissue.

scholarly journals Consecutive Prostate Cancer Specimens Revealed Increased Aldo–Keto Reductase Family 1 Member C3 Expression with Progression to Castration-Resistant Prostate Cancer

2019 ◽  
Vol 8 (5) ◽  
pp. 601 ◽  
Author(s):  
Yu Miyazaki ◽  
Yuki Teramoto ◽  
Shinsuke Shibuya ◽  
Takayuki Goto ◽  
Kosuke Okasho ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Immunohistochemical Expression ◽  
Free Survival ◽  
Castration Resistant ◽  
Psa Progression ◽  
Prostatic Epithelium

Aldo-keto reductase family 1 member C3 (AKR1C3) is an enzyme in the steroidogenesis pathway, especially in formation of testosterone and dihydrotestosterone, and is believed to have a key role in promoting prostate cancer (PCa) progression, particularly in castration-resistant prostate cancer (CRPC). This study aims to compare the expression level of AKR1C3 between benign prostatic epithelium and cancer cells, and among hormone-naïve prostate cancer (HNPC) and CRPC from the same patients, to understand the role of AKR1C3 in PCa progression. Correlation of AKR1C3 immunohistochemical expression between benign and cancerous epithelia in 134 patient specimens was analyzed. Additionally, correlation between AKR1C3 expression and prostate-specific antigen (PSA) progression-free survival (PFS) after radical prostatectomy was analyzed. Furthermore, we evaluated the consecutive prostate samples derived from 11 patients both in the hormone-naïve and castration-resistant states. AKR1C3 immunostaining of cancer epithelium was significantly stronger than that of the benign epithelia in patients with localized HNPC (p < 0.0001). High AKR1C3 expression was an independent factor of poor PSA PFS (p = 0.032). Moreover, AKR1C3 immunostaining was significantly stronger in CRPC tissues than in HNPC tissues in the same patients (p = 0.0234). Our findings demonstrate that AKR1C3 is crucial in PCa progression.

ARV7 and ARFL mRNA in blood to predict androgen receptor inhibitors and docetaxel response in castration-resistant prostate cancer patients.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 207-207
Author(s):  
Mercedes Marin ◽  
Natalia Jiménez ◽  
Òscar Reig ◽  
Maria Verónica Pereira ◽  
Maria Mila ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Mononuclear Cells ◽  
Specific Antigen ◽  
Post Treatment ◽  
Mrna Levels ◽  
Castration Resistant Prostate Cancer ◽  
Peripheral Blood Mononuclear ◽  
Castration Resistant ◽  
Docetaxel Treatment

207 Background: The constitutively active androgen receptor (AR) variant 7 ( ARV7) has been associated with AR inhibitors (ARI) resistance, while its role predicting taxanes response remains controversial. We investigated the association between ARV7 and AR full length ( ARFL) expression pre-docetaxel treatment and changes pre- post-treatment in blood with docetaxel activity in metastatic castration-resistant prostate cancer (mCRPC) patients. Methods: ARV7 and ARFL mRNAs were tested by quantitative reverse-transcription PCR in peripheral blood mononuclear cells (PBMC) from mCRPC patients. Measurements were performed before docetaxel treatment and in a subset of patients also post-treatment. A cohort of patients treated with ARI was also included as a control. Results: We included 105 patients: 50 with treated with docetaxel and 55 with ARI. In 28 patients ARV7 and ARFL were evaluated pre and post-docetaxel. High ARV7 correlated with longer PSA-PFS (HR 0.42; 95%CI 0.18-0.99; P= 0.049), radiologic (RX)-PFS (HR 0.32; 95%CI 0.14-0.72; P= 0.006), and overall survival (OS) (HR 0.41; 95%CI 0.18-0.91; P= 0.028) to docetaxel. When relativizing to ARFL we observed that high ARV7/ ARFL ratio also correlated with a better PSA-PFS (HR 0.38; 95%CI 0.17-0.85; P= 0.0179) and RX-PFS (HR 0.43; 95%CI 0.2-0.91; P= 0.0273) to docetaxel. High ARV7 and ARV7/ ARFL were correlated with lower prostatic-specific antigen (PSA) progression-free survival (PFS) to ARI therapy (HR 2.18; 95%CI 1.03-4.6; P= 0.043 and HR 3.84; 95%CI 1.54-9.4; P= 0.004, respectively). ARV7/ ARFL and treatment- ARV7/ARFL interaction were independently associated with better PSA-PFS to docetaxel treatment and lower PSA-PFS to ARI. The increase of ARV7 mRNA levels after docetaxel treatment was indicative of longer OS (HR 0.07; 95%CI 0.008-0.57; P= 0.013). Conclusions: High ARV7 expression and ARV7/ ARFL ratio evaluated in PBMC pre-docetaxel are associated with better clinical outcome in mCRPC patients and lower ARI benefit. The increase of ARV7 levels after docetaxel exposure was also indicative of better outcome.

An AKT activity threshold regulates androgen-dependent and androgen-independent PSA expression in prostate cancer cell lines

2008 ◽  
Vol 389 (6) ◽  
Author(s):  
Miltiadis Paliouras ◽  
Eleftherios P. Diamandis
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Intracellular Signaling ◽  
Specific Antigen ◽  
Independent State ◽  
Epidermal Growth ◽  
Androgen Independent

AbstractThe androgen receptor (AR) plays an important role in early prostate cancer by activating transcription of a number of genes participating in cell proliferation and growth and cancer progression. However, as the cancer progresses, prostate cancer cells transform from an androgen-dependent to an androgen-independent state. Androgen-independent prostate cancer can manifest itself in several forms, including a percentage of cancers that show reduced levels of prostate-specific antigen (PSA) and can progress without the need for the ligand or active receptor. Therefore, our goal was to examine the role of intracellular signaling pathways in an androgen-independent prostate cancerin vitromodel. Using the cell line PC3(AR)2, we stimulated cells with 5-α-dihydrotestosterone (DHT) and epidermal growth factor (EGF) and then analyzed PSA expression. We observed lower PSA expression when cells were jointly stimulated with DHT and EGF, and this was associated with an increase in AKT activity. We examined the role of AKT in AR activity and PSA expression by creating stable PC3(AR)2cell lines transfected with a PI3K-Ras-effector loop mutant. These cell lines showed lower DHT-stimulated PSA expression that correlated to changes in the phosphorylated state of AR. Therefore, we propose anin vitroandrogen-independent model in which a PI3K/AKT activity threshold and subsequent AR transactivation regulate PSA expression.

AR Copy Number and AR Signaling-directed Therapies in Castrationresistant Prostate Cancer

2018 ◽  
Vol 18 (9) ◽  
pp. 869-876
Author(s):  
Samanta Salvi ◽  
Vincenza Conteduca ◽  
Cristian Lolli ◽  
Sara Testoni ◽  
Valentina Casadio ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Copy Number ◽  
Clinical Trial Design ◽  
Complete Information ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Anti Cancer ◽  
Hormone Sensitive ◽  
Predictive And Prognostic Biomarker

Background: Adaptive upregulation of Androgen Receptor (AR) is the most common event involved in the progression from hormone sensitive to Castration-Resistant Prostate Cancer (CRPC). AR signaling remains the main target of new AR signalling-directed therapies such as abiraterone and enzalutamide in CRPC patients. Objective: In this review, we discuss general mechanisms of resistance to AR-targeted therapies, with a focus on the role of AR Copy Number (CN). We reported methods and clinical applications of AR CN evaluation in tissue and liquid biopsy, thus to have a complete information regarding its role as predictive and prognostic biomarker. Conclusion: Outcomes of CRPC patients are reported to be highly variable as the consequence of tumor heterogeneity. AR CN could contribute to patient selection and tumor monitoring in CRPC treated with new anti-cancer treatment as abiraterone and enzalutamide. Further studies to investigate AR CN effect to these agents and its potential combination with other prognostic or predictive clinical factors are necessary in the context of harmonized clinical trial design.

The Role of Chromogranin A (CgA) in Monitoring Patients with Prostate Cancer Under Androgen Deprivation Therapy: Comparison with Prostatic Specific Antigen (PSA)

2008 ◽  
Vol 1 (2) ◽  
pp. 115-119
Author(s):  
Athanasios Bantis ◽  
Petros Sountoulides ◽  
Athanasios Zissimopoulos ◽  
Christos Kalaitzis ◽  
Stilianos Giannakopoulos ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Deprivation Therapy ◽  
Chromogranin A ◽  
Specific Antigen ◽  
Androgen Deprivation ◽  
Prostatic Specific Antigen

scholarly journals Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

2019 ◽  
Vol 20 (9) ◽  
pp. 2066 ◽  
Author(s):  
Namrata Khurana ◽  
Suresh C. Sikka
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Signaling Pathways ◽  
Critical Role ◽  
Castration Resistant Prostate Cancer ◽  
Form Complex ◽  
Androgen Receptor Signaling ◽  
Castration Resistant ◽  
Signaling Axis

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

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