Upregulation of ATP Binding Cassette Subfamily C Member 5 facilitates Prostate Cancer progression and Enzalutamide resistance via the CDK1-mediated AR Ser81 Phosphorylation Pathway.

The treatment of advanced prostate cancer, castration-resistant prostate cancer, remains challenging. The mechanisms of action of ATP binding cassette subfamily C member 5 (ABCC5) in prostate cancer and its relationship with drug resistance are still unclear. Expression and prognostic analyses of ABCC5 were performed through bioinformatic methods and immunohistochemistry analyses in multiple public databases as well as in our own prostate cancer cohort. The biological function of ABCC5 in prostate cancer cells was evaluated by in vitro and in vivo cell proliferation and migration and invasion assays. The regulation of CDK1 by ABCC5 was determined via RT-qPCR, western blots, and immunofluorescence. ABCC5 was significantly overexpressed in prostate cancer and positively associated with unfavorable clinicopathological features and prognosis. Upregulation of ABCC5 could enhance the cell proliferation, migration, and invasion of prostate cancer in vitro and in vivo. Mechanistically, ABCC5 exerts a protumor effect by binding to and inhibiting the protein degradation of CDK1, which promotes the phosphorylation of AR at Ser81 by CDK1 and activates the transcriptional activity of AR on target genes. Moreover, the addition of a CDK1 inhibitor or knockdown of CDK1 significantly improved the efficacy of enzalutamide on prostate cancer cells. The ABCC5-CDK1-AR regulatory pathway could be a potential therapeutic target for advanced prostate cancer, especially castration-resistant prostate cancer (CRPC), to enhance the therapeutic effect of enzalutamide.

Comprehensive analysis of m6A regulators prognostic value in prostate cancer.

BACKGROUND: N6-methyladenosine (m6A) is the most prevalent RNA modification. While the role of m6A in prostate cancer remains unknown. We aim to measure the effects of m6A methylation regulatory genes during the development and progression of prostate cancer. METHODS: We collected transcriptome information and gene-level alteration data from The Cancer Genome Atlas datasets. The log-rank test and Cox regression model were used to examine the prognosis value of m6A methylation regulatory genes of prostate cancer. RESULTS: We discovered that most of m6A methylation regulators were highly expressed in aggressive prostate cancer. Univariable and multivariable Cox regression results showed that the expression of Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), Heterogeneous nuclear ribonucleoproteins A2/B1 (HNRNPA2B1) and N6-adenosine-methyltransferase non-catalytic subunit (METTL14) and copy number variant of AlkB Homolog 5 (ALKBH5) were considerably associated with a recurrence-free survival of prostate cancer. Furthermore, a high level of m6A methylation in mRNA promotes the progression of prostate cancer via regulating subcellular protein localization. CONCLUSION: Patients with a high level of mRNA methylation resulted from overexpression of reader proteins and methyltransferase complexes had poor survival benefits through influencing protein subcellular location in prostate cancer.

Preoperative PI-RADS Version 2 scores helps improve accuracy of clinical nomograms for predicting pelvic lymph node metastasis at radical prostatectomy.

BACKGROUND: Lymph node invasion (LNI) is a strong adverse prognostic factor in prostate cancer (PCa). The purpose of this study was to evaluate the role of Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) scores for estimating the risk of LN metastasis. The study also aimed to investigate the additional value of PI-RADSv2 scores when used in combination with clinical nomograms for the prediction of LNI in patients with PCa. METHODS: We retrospectively identified 308 patients who underwent multiparametric magnetic resonance imaging (mpMRI) and RP with pelvic lymph node dissection (PLND). Clinicopathological parameters and PI-RADSv2 scores were assessed. Univariate and multivariate logistic analyses were performed. The area under the receiver operating characteristic curves (AUCs) and decision curve analysis (DCA) were generated for assessing the incremental value of PI-RADSv2 scores combined with the Briganti and Memorial Sloan Kettering Cancer Center (MSKCC) nomograms. RESULTS: Overall, 20 (6.5%) patients had LNI. At univariate analysis, all clinicopathological characteristics and PI-RADSv2 scores were significantly associated to LNI (p < 0.04). However, multivariate analysis revealed that only PI-RADSv2 scores and percentage of positive cores were independently significant (p ≤ 0.006). The PI-RADSv2 score was the most accurate predictor (AUC, 80.2%). The threshold of PI-RADSv2 score was 5, which provided high sensitivity (18/20, 90.0%) and negative predictive value (203/205, 99.0%). When PI-RADSv2 scores were combined with Briganti and MSKCC nomograms, the AUC value increased from 75.1 to 86.3% and from 79.2 to 87.9%, respectively (p ≤ 0.001). The DCA also demonstrated that the two nomograms plus PI-RADSv2 scores improved clinical risk prediction of LNI. CONCLUSIONS: The patients with a PI-RADSv2 score <5 were associated with a very low risk of LNI in PCa. Preoperative PI-RADSv2 scores could help improve the accuracy of clinical nomograms for predicting pelvic LN metastasis at radical prostatectomy.

microRNA-183-3p Inhibits Progression of Human Prostate Cancer by Downregulating High-Mobility Group Nucleosome Binding Domain 5.

microRNAs are a class of noncoding RNAs that play important roles in cancer progression. microRNA-183-3p (miR-183-3p) is a novel microRNA that is dysregulated in many kinds of cancers. Our previous studies found high expression and oncologic role of high-mobility group nucleosome binding domain 5 (HMGN5) in prostate cancer. In this study, we found that miR-183-3p was downregulated in prostate cancer cells and primary tissues compared with normal controls. In addition, miR-183-3p expression was negatively correlated with HMGN5 expression. On the basis of bioinformatics predication and quantitative polymerase chain reaction and Western blot verification, it is demonstrated that miR-183-3p regulated HMGN5 expression. Luciferase reporter assay confirmed that miR-183-3p directly targeted the 3'-untranslated region of HMGN5. Interestingly, cell proliferation and migration inhibition and apoptosis induction were also observed in miR-183-3p transfected human prostate cancer VCap and C4-2 cells. Moreover, overexpression of HMGN5 significantly reversed the inhibitory effect on cell proliferation and migration and promoted effect on cell apoptosis by miR-183-3p. Our data suggest that dysfunction of miR-183-3p-HMGN5 axis plays an oncogenic role and can be a therapeutic target for prostate cancer.

The role of tumor size, ultrasonographic findings, and serum tumor markers in predicting the likelihood of malignant testicular histology.

The clinical predictive factors for malignant testicular histology remain unclear because of the low prevalence. Therefore, the aim of this study was to investigate predictors of malignant histology for testicular masses and decide more testis-sparing surgeries before surgery. This retrospective study enrolled 325 consecutive testicular mass patients who underwent radical orchiectomy (310/325) or testicular preserving surgery (15/325) from January 2001 to June 2016. The clinicopathological factors, including tumor diameter, cryptorchidism history, ultrasound findings, serum alpha-fetoprotein, and human chorionic gonadotropin (HCG) levels, were collected retrospectively for statistical analysis. A predictive nomogram was also generated to evaluate the quantitative probability. Among all patients, 247 (76.0%) were diagnosed with a malignant testicular tumor and 78 (24.0%) with benign histology. Larger tumor diameter (per cm increased, hazard ratio [HR] = 1.284, P = 0.036), lower ultrasound echo (HR = 3.191, P = 0.001), higher ultrasound blood flow (HR = 3.320, P < 0.001), and abnormal blood HCG (HR = 10.550, P < 0.001) were significant predictive factors for malignant disease in all testicular mass patients. The nomogram generated was well calibrated for all predictions of malignant probability, and the accuracy of the model nomogram measured by Harrell's C statistic (C-index) was 0.92. According to our data, the proportion of patients who underwent radical orchiectomy for benign tumors (24.0%) was much larger than generally believed (10.0%). Our results indicated that the diameter, ultrasonic echo, ultrasonic blood flow, and serum HCG levels could predict the malignancy in testicular mass patients.

MultiParametric Magnetic Resonance Imaging-Based Nomogram for Predicting Prostate Cancer and Clinically Significant Prostate Cancer in Men Undergoing Repeat Prostate Biopsy.

OBJECTIVE: To develop and internally validate nomograms based on multiparametric magnetic resonance imaging (mpMRI) to predict prostate cancer (PCa) and clinically significant prostate cancer (csPCa) in patients with a previous negative prostate biopsy. MATERIALS AND METHODS: The clinicopathological parameters of 231 patients who underwent a repeat systematic prostate biopsy and mpMRI were reviewed. Based on Prostate Imaging and Reporting Data System, the mpMRI results were assigned into three groups: Groups "negative," "suspicious," and "positive." Two clinical nomograms for predicting the probabilities of PCa and csPCa were constructed. The performances of nomograms were assessed using area under the receiver operating characteristic curves (AUCs), calibrations, and decision curve analysis. RESULTS: The median PSA was 15.03 ng/ml and abnormal DRE was presented in 14.3% of patients in the entire cohort. PCa was detected in 75 patients (32.5%), and 59 (25.5%) were diagnosed with csPCa. In multivariate analysis, age, prostate-specific antigen (PSA), prostate volume (PV), digital rectal examination (DRE), and mpMRI finding were significantly independent predictors for PCa and csPCa (all p < 0.01). Of those patients diagnosed with PCa or csPCa, 20/75 (26.7%) and 18/59 (30.5%) had abnormal DRE finding, respectively. Two mpMRI-based nomograms with super predictive accuracy were constructed (AUCs = 0.878 and 0.927, p < 0.001), and both exhibited excellent calibration. Decision curve analysis also demonstrated a high net benefit across a wide range of probability thresholds. CONCLUSION: mpMRI combined with age, PSA, PV, and DRE can help predict the probability of PCa and csPCa in patients who underwent a repeat systematic prostate biopsy after a previous negative biopsy. The two nomograms may aid the decision-making process in men with prior benign histology before the performance of repeat prostate biopsy.

Rapidly decreasing level of prostate-specific antigen during initial androgen deprivation therapy is a risk factor for early progression to castration-resistant prostate cancer: A retrospective study.

To build a practical model for predicting the progression to castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT).In all, 185 patients with prostate cancer who had received ADT as the primary therapy at our institution, from 2003 to 2014, were retrospectively enrolled. The following clinical variables were included in the analysis: age, clinical tumor, node, metastasis stage, Gleason score, risk groups of prostate cancer, prostate-specific antigen (PSA) at the initiation of ADT, PSA nadir after ADT, velocity of PSA decline, and the time to PSA nadir. Cox proportional-hazards regression models were calculated to estimate effects of these variables on the time of progression to CRPC.On univariate and multivariate analyses, the presence of distant metastasis before ADT (hazard ratio [HR] 6.030, 95% confidence interval (CI) 3.229-11.263, P = .001), higher PSA nadir (HR 1.185, 95% CI 1.080-1.301, P = .001), a velocity of PSA decline >11 ng/mL per month (HR 2.124, 95% CI 1.195-3.750, P = .001), and a time to PSA nadir ≤9 months (HR 0.276, 95% CI 0.162-0.469, P = .004) were significantly associated with an increased risk of progression to CRPC.Patients with a rapidly decreasing PSA level in the initial phase of ADT are more likely to progress to CRPC. Our findings provide a practical approach to screen patients during ADT for early identification of those likely to progress to CRPC, allowing treatment to be modified to improve outcomes.

Are the Pathological Characteristics of Prostate Cancer More Aggressive or More Indolent Depending upon the Patient Age?

Purpose. To identify pathological characteristics of prostate cancer according to patient age at diagnosis. Methods. A retrospective review of 2,929 men diagnosed with prostate cancer was performed. Pathological characteristics were compared across age groups: ≤55, 56-75, and >75 years. Results. The study cohort included 133 patients (4.5%), 2,033 patients (69.5%), and 763 patients (26.0%) in the three age groups, respectively. The median pathological Gleason sums in the three age groups were 8, 7, and 8, respectively. The Gleason sum, primary Gleason score, and second primary Gleason score were significantly different among the three age groups (Z = 12.975, p = 0.002; Z = 9.264, p = 0.010; Z = 6.692, p = 0.035, resp.). The percentages of Gleason pattern 5 tumors for the three age groups were 44.4%, 32.3%, and 36.8%, respectively; they were significantly different (χ2 = 11.641, p = 0.003). The percentages of tumors with Gleason score grade groups 3-5 for the three age groups were 66.9%, 60.5%, and 66.3%, respectively; they were significantly different (χ2 = 9.401, p = 0.009). Conclusions. The present study indicated that men aged ≤55 years or >75 years show higher levels of clinically significant prostate cancer compared to patients between the ages of 55 and 75 years. Younger and more elderly male patients are more likely to have a more aggressive disease.