Prostate Cancer Levels Research Articles

Regulation of protein translation and c-Jun expression by prostate tumor overexpressed 1

Prostate tumor overexpressed-1 (PTOV1), a modulator of the Mediator transcriptional regulatory complex, is expressed at high levels in prostate cancer and other neoplasias in association with a more aggressive disease. Here we show that PTOV1 interacts directly with receptor of activated protein C kinase 1 (RACK1), a regulator of protein kinase C and Jun signaling and also a component of the 40S ribosome. Consistent with this interaction, PTOV1 was associated with ribosomes and its overexpression promoted global protein synthesis in prostate cancer cells and COS-7 fibroblasts in a mTORC1-dependent manner. Transfection of ectopic PTOV1 enhanced the expression of c-Jun protein without affecting the levels of c-Jun or RACK1 mRNA. Conversely, knockdown of PTOV1 caused significant declines in global protein synthesis and c-Jun protein levels. High levels of PTOV1 stimulated the motility and invasiveness of prostate cancer cells, which required c-Jun, whereas knockdown of PTOV1 strongly inhibited the tumorigenic and metastatic potentials of PC-3 prostate cancer cells. In human prostate cancer samples, the expression of high levels of PTOV1 in primary and metastatic tumors was significantly associated with increased nuclear localization of active c-Jun. These results unveil new functions of PTOV1 in the regulation of protein translation and in the progression of prostate cancer to an invasive and metastatic disease.

Androgen Pathway Related Gene Variants and Prostate Cancer Association in Auckland Men

Multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer (PC) have been reported in statistically robust studies in the past but these require an in-depth mechanistic understanding with respect to the biological pathways leading to disease. The current study was carried out to examine the PC and benign urology disease risk associations with lifestyle, demographic and genetic factors in a group of men between the ages 40-81 years from Auckland, New Zealand. The data presented herein support a significant positive association of PC risk with tobacco smoking, and a negative association with alcohol intake. The BMI was not associated with disease risk. The SRD5A2 rs632148 G allele was associated with PC compared to those with benign urology disease, after adjustments were made for the confounding variables. The Gleason score as well as disease aggressiveness of the PC group showed no association with lifestyle, demographic factors or the SNPs studied. The levels of prostate-specific antigen (PSA) significantly increased with age, smoking status and BMI, and decreased with alcohol consumption. The AKR1C3 rs12529 G allele was significantly associated with lower PSA levels in PC and benign urology disease groups compared to healthy controls. The G allele of the SRD5A2 rs632148 SNP has shown a significant interaction with PSA and a higher Gleason score outcome. Taken together, these findings show the utility of these gene variants and patient lifestyle history, together with the diagnostic serum PSA levels, to collectively enhance the understanding of the clinical-pathological variables of PC. Such information will support the selection of more personalised treatment options for this disease greatly impacting public health. Keywords: Androgen pathway related gene variants, Gleason score, personalised medicine, prostate cancer, PSA

Comparative study of serum levels of Perforin in Prostate Cancer and Benign Prostatic Hyperplasia patients

Perforin(p) is the primary mediator of short term cytotoxicity, it is accumulated in response to proinflammatory cytokines and stored in T lymphocyte , NK cells and NKT cells are released upon activation. Perforin is a prototypical cytotoxic molecule involved in cell mediated immunity against various pathogens , alloantigens and particularly different tumors.The purpose of this study was to determine perforin level in prostate cancer (P.Ca) and Benign Prostatic Hyperplasia (BPH) This is study was performed on 59 patients consisting of 28 patients with P.Ca and 31 patients with BPH.Perforin and PSA levels were measured in cancer and BPH patients using ELISA method. Mean Perforin value was significantly lower in P.Ca patients than in BPH patients ( p < 0.01) where as mean serum PSA level was significantly higher in the cancer patients in comparison to the BPH group (P < 0.01 Our finding indicate probability of problem in expression of cytotoxic molecule ,perforin in and around the tumor.

Autophagy modulators sensitize prostate epithelial cancer cell lines to TNF-alpha-dependent apoptosis

TNF-alpha levels in prostate cancer correlate with the extent of disease and are significantly elevated in the metastatic stage. TNF receptor superfamily controls two distinct signalling cascades, leading to opposite effects, i.e. apoptosis and survival; in prostate cancer TNF-alpha-mediated signalling induces cell survival and resistance to therapy. The apoptosis of prostate epithelial cancer cells LNCaP and PC3 was investigated upon treatment with the autophagy inhibitor 3-methyladenine and the autophagy inducer rapamycin, in combination with TNF-alpha. Cells were exposed to these molecules for 18, 24 and 48 h. Autophagy was assessed via LC3 Western blot analysis; propidium iodide and TUNEL stainings followed by flow cytometry or caspase-8 and caspase-3 activation assays were performed to evaluate apoptosis. TNF-alpha-induced apoptosis was potentiated by 3-methyladenine in the androgen-responsive LNCaP cells, whereas no effect was observed in the androgen-insensitive PC3 cells. Interestingly such pro-apoptosis effect in LNCaP cells was associated with reduced c-Flip levels through proteasomal degradation via increased reactive oxygen species production and p38 activation; such c-Flip reduction was reversed in the presence of either the proteasome inhibitor MG132 or the reactive oxygen species scavenger N-acetyl-cysteine. Conversely in PC3 but not in LNCaP cells, rapamycin stimulated TNF-alpha-dependent apoptosis; such effect was associated with reduced c-Flip promoter activity and FoxO3a activation. We conclude that TNF-alpha-induced apoptosis may be potentiated, in prostate cancer epithelial cells, through autophagy modulators. Increased sensitivity to TNF-alpha-dependent apoptosis correlates with reduced c-Flip levels which are consequent to a post-transcriptional and a transcriptional mechanism in LNCaP and PC3 cells respectively.

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We appreciate the thoughtful Editorial Comment on our manuscript “The Effect of Baseline Testosterone on the Efficacy of Degarelix and Leuprolide: Further Insights from a 12-Month, Comparative, Phase III Study in Prostate Cancer Patients.” We agree that testosterone levels required after gonadotropin-releasing hormone (GnRH) manipulation merit reevaluation, especially with the availability of improved measurement techniques. Although there is currently a lack of consensus on the optimum suppressed testosterone level in prostate cancer (PCa), a 0.2 ng/mL threshold has been recommended after androgen deprivation therapy (ADT) in advanced disease. 1 Djavan B. Eastham J. Gomella L. et al. Testosterone in prostate cancer: the Bethesda consensus. BJU Int. 2011; (In press) Google Scholar Editorial CommentUrologyVol. 80Issue 1PreviewAlthough generally effective in suppressing serum androgens, gonadotropin-releasing hormone (GnRH) agonists have several liabilities that have motivated the development of alternatives. Before reducing testosterone, GnRH agonists such as leuprolide initially produce a surge in luteinizing hormone (LH), which consequently induces a transient rise in serum testosterone, an event that can result in worsening tumor-related symptoms termed a clinical flare in men with metastatic disease. Microsurges in testosterone commonly occur with repeat GnRH agonist dosing, and breakthrough rises in serum testosterone exceeding castrate levels during treatment occur in up to 13% of men. Full-Text PDF

Changes in Gene Transcription Underlying the Aberrant Citrate and Choline Metabolism in Human Prostate Cancer Samples

Low concentrations of citrate and high concentrations of choline-containing compounds (ChoCC) are metabolic characteristics observed by magnetic resonance spectroscopy of prostate cancer tissue. The objective was to investigate the gene expression changes underlying these metabolic aberrations to find regulatory genes with potential for targeted therapies. Fresh frozen samples (n = 133) from 41 patients undergoing radical prostatectomy were included. Histopathologic evaluation was carried out for each sample before a metabolic profile was obtained with high-resolution magic angle spinning (HR-MAS) spectroscopy. Following the HR-MAS, RNA was extracted from the same sample and quality controlled before carrying out microarray gene expression profiling. A partial least square statistical model was used to integrate the data sets to identify genes whose expression show significant covariance with citrate and ChoCC levels. Samples were classified as benign, n = 35; cancer of low grade (Gleason score 6), n = 24; intermediate grade (Gleason score 7), n = 41; or high grade (Gleason score ≥ 8), n = 33. RNA quality was high with a mean RNA Integrity Number score of 9.1 (SD 1.2). Gene products predicting significantly a reduced citrate level were acetyl citrate lyase (ACLY, P = 0.003) and m-aconitase (ACON, P < 0.001). The two genes whose expression most closely accompanied the increase in ChoCC were those of phospholipase A2 group VII (PLA2G7, P < 0.001) and choline kinase α (CHKA, P = 0.002). By integrating histologic, transcriptomic, and metabolic data, our study has contributed to an expanded understanding of the mechanisms underlying aberrant citrate and ChoCC levels in prostate cancer.

Positive and Negative Regulation of Prostate Stem Cell Antigen Expression by Yin Yang 1 in Prostate Epithelial Cell Lines

Prostate cancer is influenced by epigenetic modification of genes involved in cancer development and progression. Increased expression of Prostate Stem Cell Antigen (PSCA) is correlated with development of malignant human prostate cancer, while studies in mouse models suggest that decreased PSCA levels promote prostate cancer metastasis. These studies suggest that PSCA has context-dependent functions, and could be differentially regulated during tumor progression. In the present study, we identified the multi-functional transcription factor Yin Yang 1 (YY1) as a modulator of PSCA expression in prostate epithelial cell lines. Increased YY1 levels are observed in prostatic intraepithelial neoplasia (PIN) and advanced disease. We show that androgen-mediated up-regulation of PSCA in prostate epithelial cell lines is dependent on YY1. We identified two direct YY1 binding sites within the PSCA promoter, and showed that the upstream site inhibited, while the downstream site, proximal to the androgen-responsive element, stimulated PSCA promoter activity. Thus, changes in PSCA expression levels in prostate cancer may at least partly be affected by cellular levels of YY1. Our results also suggest multiple roles for YY1 in prostate cancer which may contribute to disease progression by modulation of genes such as PSCA.

351 LOWER CONCENTRATION OF SERUM INSULIN-LIKE GROWTH FACTOR IS INDEPENDENTLY ASSOCIATED WITH INCREASED RISK OF HIGH GRADE PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Epidemiology and Natural History II1 Apr 2012351 LOWER CONCENTRATION OF SERUM INSULIN-LIKE GROWTH FACTOR IS INDEPENDENTLY ASSOCIATED WITH INCREASED RISK OF HIGH GRADE PROSTATE CANCER Jongwon Kim, Wansuk Kim, Dae-Seon Yoo, Cheryn Song, Jun Hyuk Hong, Choung-Soo Kim, and Hanjong Ahn Jongwon KimJongwon Kim Seoul, Korea, Republic of More articles by this author , Wansuk KimWansuk Kim Seoul, Korea, Republic of More articles by this author , Dae-Seon YooDae-Seon Yoo Seoul, Korea, Republic of More articles by this author , Cheryn SongCheryn Song Seoul, Korea, Republic of More articles by this author , Jun Hyuk HongJun Hyuk Hong Seoul, Korea, Republic of More articles by this author , Choung-Soo KimChoung-Soo Kim Seoul, Korea, Republic of More articles by this author , and Hanjong AhnHanjong Ahn Seoul, Korea, Republic of More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.412AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES High circulating insulin-like growth factor (IGF-1) concentration is related to an increased risk of prostate cancer. Recently case-control study has reported that a strong association with IGF-1 is observed for low grade prostate cancer. We have investigated the association of IGF-1 with each Gleason score (GS) and pathologic stage of prostate cancer. METHODS Between April 2011 and August 2011, 267 patients with clinically localized prostate cancer undergoing radical prostatectomy (RP) without hormonal therapy or chemotherapy were enrolled prospectively. Total serum testosterone (TS), sex hormone-binding globulin (SHBG), IGF-1 and IGFBP-3 were measured. Binary logistic regression was used to determine the predictors for more aggressive forms of prostate cancer; high grade (pathologic GS¡Ã7) and advanced stage (nonorgan confined disease). RESULTS IGF-1 had a positive linear association with IGFBP-3 (r=0.505, p <0.001), whereas age (r=-0.318, p<0.001), TS (r=-0.278, p<0.001), and SHBG (r=-0.364, p<0.001) were inversely associated with IGF-1. Concentration of IGF-1 was significantly higher in low grade tumor (158.6 vs. 137.0 ng/mL, p=0.01) compared to that in high grade tumor, whereas TS, SHBG and IGFBP-3 were not significantly different. In multivariate analysis, low concentration of IGF-1 as a continuous variable was a significant predictor of high grade tumor (OR=0.993, 95%CI=0.986-1.000, p=0.036) after adjusting for age, diabetes, body mass index, TS, SHBG and IGFBP-3. Patients with IGF-1 below 110 ng/mL had a 2.8-fold elevation in risk of high grade tumor compared to those with higher concentrations (95%CI=1.061-7.478, p=0.038). However neither IGF-1 nor IGFBP-3 was observed to be significantly associated with pathologic stage of prostate cancer. CONCLUSIONS Lower concentration of serum IGF-1 is independently associated with an increased risk of high grade tumor. Although the exact biologic mechanism remains to be elucidated, IGF-1 might regulate the level of bioactive TS decreasing SHBG level in prostate cancer. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e142-e143 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jongwon Kim Seoul, Korea, Republic of More articles by this author Wansuk Kim Seoul, Korea, Republic of More articles by this author Dae-Seon Yoo Seoul, Korea, Republic of More articles by this author Cheryn Song Seoul, Korea, Republic of More articles by this author Jun Hyuk Hong Seoul, Korea, Republic of More articles by this author Choung-Soo Kim Seoul, Korea, Republic of More articles by this author Hanjong Ahn Seoul, Korea, Republic of More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Variations of serum testosterone levels in prostate cancer patients under LH-releasing hormone therapy: an open question

The hypothesis 'the lower the better when achieving castration levels of testosterone' is based on the data from second-line hormonal manipulation and its molecular basis, and on better oncological results reported for lower castration levels in prostate cancer (PCa) patients, including those achieved with maximal androgen blockade. In this regard, the equivalence of surgical and different pharmacological castrations has been controversial. The modified amino acid structure that makes LH-releasing hormone (LHRH) analogs more potent than LHRH, and the method of delivering the analogs impacts on bioavailibility and potentially causes differences in androgen levels and in its final oncological efficacy. In addition to this, there is a myriad of circumstances, such as those related to ethnic variations and co-morbidities, which uniquely impact on the pharmacological approach in a highly heterogeneous population of castration-resistant prostate cancer (CRPC) patients. Ineffective testosterone suppression through hormonal escape is currently poorly recognized and may result in increased PCa mortality. Until now, the optimal serum testosterone level in patients under castration, and the impact of its variations in patients under LHRH therapy, remain open questions and have been merged to a broad spectra of patients who are highly heterogeneous. This heterogeneity relates to a number of mechanisms regarding response to treatment, which influences the biology of the relapsing tumor and the sensitivity to subsequent therapies in the individual patient. The rationale to achieve testosterone levels below 20-50 ng/dl warrant further investigation as these levels have recently rescued CRPC patients. In the last few years and months, important advancements in prostate cancer treatment have been achieved. Nevertheless, these advances are measured in a few months of additional survival and under high costs, not available to most of the world population, compared with the benefits of hormonal manipulation that are measured in years, there is a huge potential for accessible and durable effect expansion and optimization of treatment, particularly with the current tendency of a more individual approach.

Correlation of AR, EGFR, and HER2 Expression Levels in Prostate Cancer: Immunohistochemical Analysis and Chromogenic In Situ Hybridization

PurposeThe androgen receptor (AR) plays a central role in prostate cancer. Evidence from several groups indicates that epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) may enhance AR activity in prostate cancer cell lines. This study was designed to investigate the protein expression of AR, EGFR, and HER2 and to determine whether the EGFR and HER2 genes are amplified in prostate cancer tissues.Materials and MethodsThe protein expression levels of AR, EGFR, and HER2 in a tissue microarray block of 66 prostate cancer samples were investigated by immunohistochemical analysis and chromogenic in situ hybridization was used to determine whether the EGFR and HER2 genes were amplified in these tissues.ResultsThe AR and EGFR proteins were expressed in 59.1% and 40.9% of prostate cancers, respectively, but their expression levels were not significantly associated with clinicopathologic factors. Of the cases in which tissues were negative for EGFR protein expression, 69.2% were positive for AR protein expression; however, AR protein expression was significantly reduced (44.4%) in tissues in which EGFR protein was expressed. HER2 expression was detected in only 1 case (1.5%). No amplification of the EGFR or HER2 genes was found in prostate cancer specimens.ConclusionThis study was limited by small number of subjects, but it can still be inferred that the expression levels of the AR and EGFR proteins are inversely correlated in prostate cancer patients. The potential utility of EGFR and HER2 as prognostic factors or therapeutic targets warrants further study.

68Ga]Gallium-labelled PSMA ligand as superior PET tracer for the diagnosis of prostate cancer: comparison with 18F-FECH

Prostate-specific membrane antigen (PSMA) is a cell surface protein, which is expressed at higher levels in prostate cancer compared to other tissues. This protein provides a promising target for specific imaging and therapy due to its transmembrane location and internalization after ligand binding [1]. PSMA is also expressed in the neovasculature of many solid tumours [2, 3]. Recently procedures have been developed to label PSMA with Ga and I for positron emission tomography (PET) imaging [4, 5]. We present for the first time PET/CT images obtained with Ga-labelled HBED-CC conjugate of the PSMA-specific pharmacophore Glu-NH-CO-NH-Lys (Ga-PSMA). The images were compared with [F]FECH PET/CT of the same patient. The 67-year-old patient had undergone previous radiotherapy of the prostate due to carcinoma and had received androgen therapy since 2002. The patient presented with a continuous increase of PSA values (from 1 ng/ml in 2002 to 7.4 ng/ml in May 2011) and was referred to our department for further analysis using PET/CT. F-FECH PET/CT was unable to detect any lesions. However, Ga-PSMA PET/CT did show a lesion adjacent to the urinary bladder compatible with tumour relapse (figure). Our initial experience with Ga-PSMA PET/CT strongly suggests that this novel method can detect prostate carcinoma relapses and metastases with significantly improved contrast compared to F-FECH PET/CT. Further clinical studies should confirm this observation and determine if PSMA PET/CT can replace F-FECH PET/CT in the diagnosis of prostate carcinoma.

Biochemical relapse following radical prostatectomy and miR‐200a levels in prostate cancer

Radical prostatectomy cures the majority of men with clinically localized disease, but up to 30% of men relapse with rising serum PSA levels. Stage, Gleason grade, and pre-operative PSA levels are associated with outcome but do not accurately predict which individuals will relapse. MicroRNA (miRNA) levels are altered in cancer and are associated with progression of disease. The miR-200 family has roles in prostate cancer. miR-200a levels were measured in 18 radical prostatectomy samples from men who did not relapse and from 18 who did relapse, matched for stage (all T3), grade, and PSA levels. A pair of cancer and normal prostate cell lines derived from the same radical prostatectomy specimen were transfected with miR-200a to determine the effects on growth, wound healing, and invasion. Comparing the matched samples, 11 of the relapsers contained lower, 2 higher and 5 similar levels to the non-relapsers. Transient transfection of miR-200a significantly reduced cell proliferation in prostate cancer cell lines but did not affect invasiveness. miR-200a overexpression reduced prostate cancer cell growth and may have potential, in combination with other markers, in stratifying prostate cancer patients for more intensive monitoring and therapy.

XPA-210: a new proliferation marker determines locally advanced prostate cancer and is a predictor of biochemical recurrence

XPA-210 is a proliferation marker derived from Thymidine kinase-1. It is of clinical significance in kidney, breast, and bladder cancer. There are no data available for XPA-210 in prostate cancer (PC). Herein, we aim to determine the clinical usefulness of XPA-210 in PC. In a retrospective study, cancer and benign tissue samples of 103 patients (median age 65years, median PSA 9.04ng/ml, median Gleason score 6) who underwent prostatectomy were constructed to a tissue micro array and stained for XPA-210. Semi-quantitative results were correlated with pathological and clinical data by Wilcoxon-Kruskall-Wallis and linear regression analysis. Expression levels in PC were correlated between the time of biochemical recurrence and the time to development of metastasis by the Kaplan-Meier method. Multivariate analysis was done to correlate those with the resection status. Mean staining score was 0.51-0.14 for tumor and benign tissue (P<0.0001). Tumor staining score was significantly associated with Gleason score <6/≥6 (P<0.0001) and T2/T>2 (P=0.0007). When dividing the tumor score by the mean value, higher expression of XPA-210 was associated with a shorter time to biochemical recurrence (P=0.003) and time to development of metastasis (P=0.0061). Tumor staining (P=0.0371) was an independent prognostic factor for biochemical relapse regardless of resection status. XPA-210 is a new tissue-based prognostic marker for prostate cancer histopathology. It reliably differentiates tumor and normal prostatic tissue predicting biochemical relapse and onset of metastatic disease. XPA-210 might be clinically useful for individual decision-making in PC-treatment.

Prospective Phase II Study Evaluating the Relationship of Fatigue and Plasma Inflammatory Cytokine Levels in Prostate Cancer (PC) Patients Undergoing External Beam Radiation Therapy (EBRT)

Cancer patients undergoing EBRT experience significant fatigue during treatment that negatively impacts physical functioning and quality of life (QOL). Our hypothesis was that EBRT-induced increases in inflammatory cytokines resulting from tissue toxicity play an important mechanistic role in treatment-related fatigue. We undertook a prospective, longitudinal, single arm, Phase II study with specific aims to evaluate the relationship between cytokines, patient activity levels, and self-reported fatigue-related symptoms during a standard course of EBRT for PC. 28 men undergoing EBRT for low to intermediate risk PC without androgen therapy (ADT) were accrued onto an institutional review board-approved prospective clinical trial. Participants used an Actiwatch Score (MiniMitter/Respironics Inc.) to record their daily fatigue level, on a 1 - 10 scale (1 = no fatigue, 10 = worst fatigue), prior to and during EBRT to 78 Gy at 2 Gy/fraction. Peripheral blood was collected immediately prior to the 1st treatment and then after the 5th, 15th, 25th, and 39th treatment. Cytokine analysis was performed using a bead based immunofluorescence assay (Luminex Inc.) for serum IL-1α, IL-1β, TNF-α, IL-6, IL-8, IL-10 and VEGF. Area under the curve analysis with respect to total (AUCt) across the repeated measures was computed for fatigue and serum cytokine response measures. Multiple regressions were used to test the relationship between the serum cytokine response and fatigue measures. Participants were 96% Caucasian with an average age of 66.8 yrs (range 58 - 81). Gleason Score = 6 - 7, clinical stage = T1c - T2b, and initial average PSA = 7.7 ng/mL. Average pre-treatment levels of fatigue were 2 ± 1. We observed a significant correlation between pre-treatment levels of fatigue and serum levels of IL-6 (r = 0.42, p = 0.026), IL-1α (r = 0.408, p = 0.031), and VEGF (r = 0.42, p = 0.023). The average change in fatigue level by the end of treatment was 1.4 ± 1.8. The only significant correlation identified was between total IL-6 and total fatigue response to treatment (r = 0.396, p = 0.041). The observed relationship between serum IL-6 levels and fatigue is consistent with existing studies in cancer patients. None of the other inflammatory cytokines analyzed were associated with fatigue response during treatment. This lack of an association may be related to small sample size or the relatively small average increase in fatigue level during treatment Our study establishes a feasible model for prospectively evaluating activity, symptoms, and cytokines related to fatigue that serves as a standard for future protocols.

The Risk of Prostate Cancer from Occupational Exposures in Male Firefighters

Prostate cancer is the most commonly diagnosed cancer among men. Since prostate cancer is a slow developing cancer, mortality can be prevented if the tumour is detected and treated in its early stages. There is proof that environmental exposures can increase the risk of prostate cancer. Many papers have performed data analyses on prostate cancer levels in firefighters. There has been some research on firefighter prostate cancer levels but few reviews on the topic. This paper focuses on finding whether there is a correlation between firefighting occupation and levels of prostate cancer. As well, this paper notes potential carcinogens within the firefighting occupation. Five papers were included in this review; these papers used different methods to obtain the cases and cohorts for the study. The papers also used different controls for comparison. Nevertheless, the papers found in the search supported a positive correlation between exposures in firefighting occupations and the level of prostate cancer. The two chemicals that were suspected carcinogens in these studies were Polyaromatic hydrocarbons (PAH) and fire smoke. However, future research can be more rigorous in calculations of prostate cancer levels by including lifestyle factors, other confounders such as smoking, and estimated length of exposure.

TM4SF1, a novel primary androgen receptor target gene over‐expressed in human prostate cancer and involved in cell migration

The Androgen Receptor (AR) plays a key role in controlling prostate gland homeostasis and contributes to prostate carcinogenesis. The identification of its target genes should provide new candidates that may be implicated in cancer initiation and progression. Transcriptomic experiments and chromatin immunoprecipitation were combined to identify direct androgen regulated genes. Real-time quantitative PCR (RT-qPCR) analyses were performed to measure TM4SF1 mRNA levels in prostate cancer and benign prostatic hyperplasia (BPH) specimens. Immunohistochemical methods were used to compare TM4SF1 protein expression profiles in the same cohort. A targeted siRNAs knockdown strategy was used, prior to wound healing assays, to analyze the role of TM4SF1 in cell migration in vitro. We demonstrate for the first time that TM4SF1 is a direct target gene of the AR, a transcription factor of the steroid nuclear receptor family. A functional androgen response element was identified in the promoter region of the gene. In addition, TM4SF1 mRNA expression was higher in cancer samples compared to BPH tissues. The TM4SF1 protein mediates cell motility of prostate cancer cells where it is predominantly localized in the cytoplasm, in contrast to its apical membrane localization in normal prostate epithelial cells. Our results reveal a novel function for TM4SF1 in AR signaling. The TM4SF1 mRNA expression is higher in prostate cancer tissues as compared to BPH samples. Inhibition of cell migration after targeted knockdown of TM4SF1 protein expression suggests its contribution to prostate cancer cell metastasis.

The relationship between proangiogenic gene expression levels in prostate cancer and their prognostic value for clinical outcomes

Androgens stimulate the expression of vascular endothelial growth factor (VEGF) through activation of hypoxia inducible factor (HIF). These genes play a major role in cancer angiogenesis. This study assesses the relationship among expression levels for the androgen receptor (AR), HIF1a, VEGF-A, and VEGF-C genes in human prostate cancer tissue and their impact on prostate cancer outcomes. It also examines the impact of pre-operative androgen deprivation therapy (ADT) on the expression of these genes. Radical prostatectomy specimens were obtained from 138 patients with D1 prostate cancer from the University of Southern California prostatectomy database; 30% received pre-operative and 23% received post-operative ADT. Gene expression levels were determined by quantitative real-time PCR. Specimens were stratified into three groups for each gene based on expression levels, and groups were compared for clinical outcomes (PSA and clinical recurrence, overall survival). There was a significant correlation in expression levels amongst all genes. Patients treated with pre-operative ADT had significantly lower HIF1a expression, mean 2.64 (CI 2.34-2.94) than patients not treated, mean 3.25 (CI 2.97-3.53, P = 0.006), adjusting for age, PSA, Gleason score, and stage. Higher VEGF-A expression was significantly associated with better overall survival (HR 0.49, P = 0.015). The risk of developing clinical recurrence was significantly lower with higher VEGF-C expression (HR 0.4, P = 0.014). Significant correlation was noted among AR, HIF1a, VEGF-A, and VEGF-C. This study shows that ADT is associated with lower HIF1a gene expression in human prostate cancer tissue and documents prognostic value for VEGF-A and VEGF-C expression levels.

Androgen receptor expression is associated with prostate cancer‐specific survival in castrate patients with metastatic disease

To investigate whether baseline (before treatment) clinical variables and tumour specimen characteristics (including the androgen receptor, AR) from patients with castrate-resistant metastatic prostate cancer can be used to predict the time to prostate cancer-specific mortality and overall survival, as AR levels in prostate cancer have been associated with disease progression, including prostate-specific antigen (PSA) recurrence and systemic metastasis. Haematoxylin and eosin (H&E) slides/blocks and outcome data from a 104 castrate patients with metastatic disease (43 prostatectomy and 61 prostate needle biopsy samples), were independently reviewed; H&E morphometry and quantitative immunofluorescence were used to assess the samples. Sections were analysed with a multiplex quantitative immunofluorescence (IF) assay for cytokeratin-18 (epithelial cells), 4',6-diamidino-2-phenylindole (nuclei), p63/high molecular weight keratin (basal cells), AR and alpha-methyl CoA-racemase. Images were acquired with spectral imaging software and processed for quantification with IF algorithms. The median follow-up was 12 years from diagnosis; 49 men (47%) baseline PSA levels of > or = 20 ng/mL, 55 (53%) had a Gleason sum of 8, 63 (60%) died from the disease and 40% were alive (censored). In all, 66 patients had evaluable IF features, and the association with outcome was evaluated by univariate Cox modelling and support-vector regression. PSA was the only clinical variable associated with outcome (concordance index, CoI, 0.41; P < 0.05, log-rank test). The amount of AR present within tumour nuclei (regardless of tissue provenance and primary treatment) significantly correlated with a greater risk of a shorter time to prostate cancer-specific mortality (CoI 0.36; P < 0.05 log-rank test). There were no H&E features that correlated with mortality. By univariate analysis, increased nuclear AR expression in either the diagnostic biopsy and/or radical prostatectomy specimen, from patients with advanced disease, was associated with a reduced time to prostate cancer-specific mortality.

Targeted Knockdown of EGR-1 Inhibits IL-8 Production and IL-8-mediated Invasion of Prostate Cancer Cells through Suppressing EGR-1/NF-κB Synergy

IL-8 produced by prostate cancer cells may be responsible for the androgen-independent growth of advanced prostate cancers. Accumulating evidence from microarray analyses and animal genetic models highlights the central involvement of the transcription factor early growth response-1 (EGR-1) in prostate carcinoma progression. It is unknown, however, whether knockdown of EGR-1 inhibits IL-8 production and IL-8-mediated tumor metastasis. Here we show that EGR-1 knockdown by a specific shRNA-Egr1 inhibited gene transcription and production of IL-8 by the human prostate cancer cell line DU145. Conversely, enforced expression of EGR-1 in EGR-1-lacking PC3 prostate cancer cells markedly enhanced IL-8 transcription and secretion. By using wild type and a series of mutant IL-8 promoter luciferase constructs, we found that the NF-kappaB binding site is important for EGR-1 regulation of IL-8. Furthermore, silencing EGR-1 suppressed a synergistically functional interaction between EGR-1 and NF-kappaB. Consequently, knockdown of EGR-1 inhibited IL-8-mediated tumor colony formation and invasion. Thus, targeted knockdown of EGR-1 could be an effective therapeutic approach against prostate cancer.

Transcription variants of the prostate-specific PrLZ gene and their interaction with 14-3-3 proteins

We have reported isolation and characterization of the prostate-specific and androgen-regulated PrLZ gene abnormally expressed in prostate cancer. PrLZ is a potential biomarker for prostate cancer and a candidate oncogene promoting cell proliferation and survival in prostate cancer cells. A full delineation of the PrLZ gene and its gene products may provide clues to the mechanisms regulating its expression and function. In this report, we identified three additional exons in the PrLZ gene and recognized five transcript variants from alternative splicing that could be detected by RT-PCR and Western blotting. Structural comparison demonstrated that the PrLZ proteins are highly conserved among species. PrLZ contains multiple potential sites for interaction with other proteins. We used mammalian two-hybrid assays to demonstrate that PrLZ isoforms interact with 14-3-3 proteins, and multiple sites in the PrLZ may be involved in the interaction. Alternative splicing may contribute to abnormally enhanced PrLZ levels in prostate cancer, and interaction with 14-3-3 proteins may be a mechanism by which PrLZ promotes cell proliferation and survival during prostate cancer development and progression. This information is a valuable addition to the investigation of the oncogenic properties of the PrLZ gene.