Clinical Prostate Cancer Research Articles

Overexpression of RACGAP1 by E2F1 Promotes Neuroendocrine Differentiation of Prostate Cancer by Stabilizing EZH2 Expression.

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. It is characterized by the loss of androgen receptor (AR) signaling in neuroendocrine transdifferentiation, and finally, resistance to AR-targeted therapy. With the application of a new generation of potent AR inhibitors, the incidence of NEPC is gradually increasing. The molecular mechanism of neuroendocrine differentiation (NED) after androgen deprivation therapy (ADT) remains largely unclear. In this study, using NEPC-related genome sequencing database analyses, we screened RACGAP1, a common differentially expressed gene. We investigated RACGAP1 expression in clinical prostate cancer specimens by IHC. Regulated pathways were examined by Western blotting, qRT-PCR, luciferase reporter, chromatin immunoprecipitation, and immunoprecipitation assays. The corresponding function of RACGAP1 in prostate cancer was analyzed by CCK-8 and Transwell assays. The changes of neuroendocrine markers and AR expression in C4-2-R and C4-2B-R cells were detected in vitro. We confirmed that RACGAP1 contributed to NE transdifferentiation of prostate cancer. Patients with high tumor RACGAP1 expression had shorter relapse-free survival time. The expression of RACGAP1 was induced by E2F1. RACGAP1 promoted neuroendocrine transdifferentiation of prostate cancer by stabilizing EZH2 expression in the ubiquitin-proteasome pathway. Moreover, overexpression of RACGAP1 promoted enzalutamide resistance of castration-resistant prostate cancer (CRPC) cells. Our results showed that the upregulation of RACGAP1 by E2F1 increased EZH2 expression, which drove NEPC progression. This study explored the molecular mechanism of NED and may provide novel methods and ideas for targeted therapy of NEPC.

Sensitive electrochemical sensing platform based on Au nanoflower-integrated carbon fiber for detecting interleukin-6 in human serum

Prostate cancer (PCa) is the most prevalent cancer worldwide, with a high mortality rate. The early and accurate detection of PCa is critical in reducing mortality and saving lives. Timely diagnosis can improve the chances of successful treatment using advanced technologies. In recent years, nanomaterial-based electrochemical sensing strategies have been adopted in clinical diagnosis, as they allow sensitive early-biomarker detections to be converged with a cost-effective electronic readout system. Herein, we present a flexible electrochemical immunosensor platform for detecting interleukin-6 (IL-6) based on an Au-integrated flexible carbon fiber (Au/CF) electrode prepared via electrodeposition and chemically modified to capture IL-6 antibodies. Several techniques are used to analyze the prepared Au/CF composite electrodes to confirm their morphology, structure, and elemental composition. Under optimum conditions, the fabricated immunosensor exhibits a wide linear dynamic ranging from 1 fg/mL to 1 μg/mL and a low detection limit of 0.056 fg/mL, with a sensitivity of 62.17 μA/(fg mL−1). The proposed fiber-based immunosensor is used to quantify the concentration of IL-6 in serum samples from clinical PCa patients (T3b and T4 stages), and the results are validated using the commercial Meso Scale Diagnostics (MSD) V-Plex method. The acceptable results yielded by the proposed immunosensor indicate that it can serve as a new platform to realize highly sensitive and cost-effective diagnostic strategies for the early diagnosis of PCa.

The Use of HA as Rectal Spacer in Prostate Cancer Patients Undergoing Hypofractionated RT: An Australian Experience

<h3>Purpose/Objective(s)</h3> To report the feasibility, post-operative complications and recto-prostatic separation achieved with hyaluronic acid (HA) inserted into the perirectal fat before definitive prostate radiotherapy (RT). <h3>Materials/Methods</h3> Fifty-seven patients with clinical stage T1-3 prostate cancer underwent transrectal ultrasound guided transperineal insertion of fiducial markers and HA into the perirectal space before volumetric arc RT between 7/2020 to 7/2021. Post insertion computerized tomography (CT) and magnetic resonance imaging (MRI) scans were obtained for treatment planning. HA feasibility, safety and recto-prostatic separation were assessed. The prescribed dose to the planning target volume (PTV) ranged from 60-62Gy in 20 fractions. <h3>Results</h3> The mean age was 74.7 years. The median PSA was 8.1 [Interquartile range (IQR)6.2-10.0]. The majority of patients had ISUP 2 adenocarcinoma (60%). The rest had ISUP 1 (11%) and ISUP 3 (30%). The disease risk was staged as early in 11%, favorable intermediate in 30%, unfavorable intermediate in 58% and high in 2%. Androgen deprivation therapy was delivered in 63%. HA insertion was completed with a 100% success rate. This was rated as ‘easy' to ‘very easy' 100% of the time. There were no device related complications, rectal perforation, serious bleeding, infections or allergic reactions. The mean prostate size was 43cc (IQR 30-55cc). Recto-prostatic separation at the base (measured 5mm below the prostate base), mid gland and apex (measured 5mm above the prostate apex) were 12mm (0.2), 11mm (0.2) and 0.9mm (0.1) respectively. The HA was also symmetrically placed in breadth at the mid gland in all patients. The mean rectal volume receiving 53Gy (rV53) was 3.2% (IQR 1.3-5.5) for patients receiving 60-62Gy. The median follow up was 13.5 months (IQR 9.5-17.5). The risk of any acute GU toxicity was 81%. The majority had grade 1 GU toxicity at 67% with urinary frequency, urgency and obstruction being the commonest reported side effects. The risk of any grade 2 GU toxicity was 14% with urinary obstruction (13%) and urgency (7%). The risk of any acute GI toxicity was 2%. Only 1 patient developed grade 1 GI toxicity with diarrhea. The risk of any late GU toxicity was 43%. The majority had grade 1 GU toxicity at 32% with urinary frequency, urgency and obstruction. The risk of any grade 2 GU toxicity was 11% with urinary obstruction (5%), urgency (5%) and incontinence (2%). The risk of any late GI toxicity was 2%. Only 1 patient had grade 1 GI toxicity with diarrhea. <h3>Conclusion</h3> HA was successfully inserted in all patients and was well tolerated. Recto-prostatic separation was symmetrical in length from the base to the apex and in breadth at the midgland. The risk of developing any acute GI toxicity was minimal at 2% with the use of HA. In addition, the risk of late GI toxicity was 2%, albeit with short follow up.

Study on the role of SLC14A1 gene in biochemical recurrence of prostate cancer

Prostate cancer (PCa) is a common malignant disease among men and biochemical recurrence (BCR) is considered to be a decisive risk factor for clinical recurrence and PCa metastasis. Clarifying the genes related to BCR and its possible pathways is vital for providing diagnosis and treatment methods to delay the progress of BCR. An analysis of data concerning PCa from previous datasets of The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) was performed. Immunohistochemical (IHC) staining were used to evaluate the expression of SLC14A1 in prostate tissues. Kaplan–Meier analysis, Pearson correlation, and single sample Gene Set Enrichment Analysis (ssGSEA) were used to identify the potential pathway and molecular mechanism of the function of SLC14A1 in BCR of PCa. The expression of SLC14A1 is significantly reduced in prostate cancer cells and tissue comparing to normal prostate epithelial cell and para-cancerous tissue. As indicated by Kaplan–Meier analysis, High expression of SLC14A1 could increase the BCR-free survival time of PCa patients. This effect might be related to the interaction with miRNAs (has-miR-508, has-mir-514a2, and has-mir-449a) and the infiltration of B cells. SLC14A1 is a novel important gene associated with BCR of PCa, and further studies of its molecular mechanism may delay the progress of BCR.

O07 - Ribosomal 2’-O-methylation profiling reveals cancer-associated ribosomal signature in clinical prostate cancer

O07 - Ribosomal 2’-O-methylation profiling reveals cancer-associated ribosomal signature in clinical prostate cancer

SC238 - Survival after radical prostatectomy vs. radiation therapy in clinical node-positive prostate cancer

SC238 - Survival after radical prostatectomy vs. radiation therapy in clinical node-positive prostate cancer

Outcome of Patients With Elevated Prostate-Specific Antigen and Lower Urinary Tract Symptoms Receiving Holmium Laser Enucleation of the Prostate.

PurposeThis study investigated functional outcomes in lower urinary tract symptoms (LUTS), the incidence of incidental prostate cancer (PCa), and changes in prostate-specific antigen (PSA) levels after holmium laser enucleation of the prostate (HoLEP) in patients with elevated PSA and benign prostatic hyperplasia (BPH).MethodsA retrospective review of a prospectively designed protocol for patients who underwent HoLEP at our institution from January 2010 to May 2020 was conducted. Patients were classified into low-PSA (<3.0 ng/mL) and high-PSA (≥3.0 ng/mL) groups at baseline. Follow-up for PSA was performed at the sixth postoperative month. Baseline and postoperative clinical parameters, functional parameters, PCa incidence, and postoperative changes in PSA were compared between the low- and high-PSA groups.ResultsThe baseline PSA of 1,296 patients (mean age, 69.7±6.8 years) was 4.0±4.1 ng/mL, with 712 patients (55.0%) in the low-PSA group (1.6±0.8 ng/mL), and 584 patients (45.0%) in the high-PSA group (6.9±4.7 ng/mL). Incidental PCa was detected in 82 patients (6.3%), with a similar incidence in the low-PSA (41 patients, 5.9%) and high-PSA (41 patients, 7.0%) groups (P>0.05). At 6 months postoperatively, both groups showed significant improvements in the maximum flow rate, postvoid residual volume, and all domains of the International Prostate Symptom Score (P<0.05). At postoperative 6 months, the PSA level significantly decreased by 66.6%±23.6% in all patients (54.3%±23.9% in the low-PSA group; 79.6%±14.7% in the high-PSA group) (P<0.05), and the PSA levels of 1,264 patients (97.6%) had normalized.ConclusionsIn patients with elevated PSA presenting with LUTS/BPH, our study demonstrated significant improvements in functional parameters and decreased PSA after HoLEP. The incidental PCa detection rate did not show a statistically significant difference between the low- and high-PSA groups. Timely surgery for LUTS/BPH without delay due to PSA monitoring should be considered.

Histone lysine methylation patterns in prostate cancer microenvironment infiltration: Integrated bioinformatic analysis and histological validation.

BackgroundEpigenetic reprogramming through dysregulated histone lysine methylation (HLM) plays a crucial role in prostate cancer (PCa) progression. This study aimed to comprehensively evaluate HLM modification patterns in PCa microenvironment infiltration.Materials and methodsNinety-one HLM regulators in The Cancer Genome Atlas (TCGA) dataset were analyzed using bioinformatics. Differentially expressed genes (DEGs) and survival analyses were performed using TCGA-PRAD clinicopathologic and follow-up information. Consensus clustering analysis divided patients into subgroups. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the DEGs. Tumor mutation burden (TMB) and tumor microenvironment (TME) cell infiltration were evaluated in different HLM clusters. Quantitative real-time PCR (qPCR) analysis assessed HLM regulators in clinical PCa tissues.ResultsThe tumor vs. normal (TN), Gleason score (GS) > 7 vs. GS < 7, pathological T stage (pT) = 2 vs. pT = 3, and TP53 mutation vs. wild-type comparisons using TCGA-PRAD dataset revealed 3 intersecting HLM regulators (EZH2, NSD2, and KMT5C) that were consistently upregulated in advanced PCa (GS > 7, pT3, HR > 1, and TP53 mutation) (P < 0.05) and verified in clinical PCa tissues. Consensus clustering analysis revealed three distinct HLM modification patterns (HLMclusters). However, no significant differences in recurrence-free survival (RFS) rates were found among the groups (P > 0.05). We screened 189 HLM phenotype-related genes that overlapped in the pairwise comparisons of HLMclusters and P < 0.01 in the Cox regression analysis. Three distinct subgroups (geneClusters) were revealed based on the 189 genes, in which cluster A involved the most advanced PCa (PSA > 10, T3-4, GS8-10, and biochemical recurrence) and the poorest RFS. The HLM score (HLMscore) was calculated by principal component analysis (PCA) of HLM phenotype-related genes that have positive predictive value for RFS (P < 0.001) and immune therapy responses (in the CTLA4-positive and -negative responses accompanied by a PD1-negative response).ConclusionWe comprehensively evaluated HLM regulators in the PCa microenvironment using TCGA-PRAD, revealing a nonnegligible role of HLM patterns in PCa complexity and heterogeneity. Elucidating the effects of HLM regulators in PCa may enhance prognostics, aggressiveness assessments, and immunotherapy strategies.

Prostate cancer resistance leads to a global deregulation of translation factors and unconventional translation.

Emerging evidence associates translation factors and regulators to tumorigenesis. However, our understanding of translational changes in cancer resistance is still limited. Here, we generated an enzalutamide-resistant prostate cancer (PCa) model, which recapitulated key features of clinical enzalutamide-resistant PCa. Using this model and poly(ribo)some profiling, we investigated global translation changes that occur during acquisition of PCa resistance. We found that enzalutamide-resistant cells exhibit an overall decrease in mRNA translation with a specific deregulation in the abundance of proteins involved in mitochondrial processes and in translational regulation. However, several mRNAs escape this translational downregulation and are nonetheless bound to heavy polysomes in enzalutamide-resistant cells suggesting active translation. Moreover, expressing these corresponding genes in enzalutamide-sensitive cells promotes resistance to enzalutamide treatment. We also found increased association of long non-coding RNAs (lncRNAs) with heavy polysomes in enzalutamide-resistant cells, suggesting that some lncRNAs are actively translated during enzalutamide resistance. Consistent with these findings, expressing the predicted coding sequences of known lncRNAs JPX, CRNDE and LINC00467 in enzalutamide-sensitive cells drove resistance to enzalutamide. Taken together, this suggests that aberrant translation of specific mRNAs and lncRNAs is a strong indicator of PCa enzalutamide resistance, which points towards novel therapeutic avenues that may target enzalutamide-resistant PCa.

HMGB1 promotes the development of castration‑resistant prostate cancer by regulating androgen receptor activation.

AR signalling pathway reactivation plays a key role in the development of castration-resistant prostate cancer (CRPC). High-mobility group protein B1 (HMGB1) is an important factor involved in the occurrence and development of a variety of tumours by regulating gene transcription. In the present study, the association between HMGB1 and prostate cancer (PCa) and the effects of HMGB1 on androgen receptor (AR) transcription and signalling pathway reactivation in PCa cells in vitro and in vivo were evaluated. A bioinformatics method was used to determine the mRNA expression level of HMGB1 in PCa specimens and its correlation with the mRNA expression of AR. Immunohistochemical staining was used to detect the expression of these proteins in clinical PCa samples. Reporter gene and ChIP assays were performed to determine the activity of AR and the effect of HMGB1 on the ability of AR to bind to the promoters of prostate specific antigen and transmembrane protease, serine 2. A bioluminescence resonance energy transfer assay was employed to observe the direct interaction between HMGB1 and AR protein. Additionally, a castrated nude mouse xenograft tumour model was established to verify the effect of HMGB1 on PCa. The results revealed that HMGB1 expression was significantly increased in PCa specimens, which may have a strong correlation with AR expression. Moreover, HMGB1 could reactivate the AR signalling pathway, directly interact with AR, and promote the development of CRPC in an androgen-independent manner. The results of the present study indicated that HMGB1 promoted the development of CRPC by interacting with AR, which inferred that decreasing the expression of HMGB1 may be a potential effective method for CRPC prevention and treatment.

Comparison of malignancy and spatial distribution between latent and clinical prostate cancer: an 8-year biopsy study

BackgroundCurrent prostate cancer (PCa) screening may detect nonprogressive lesion, leading to overdiagnosis and overtreatment. The purpose of the present study is to investigate whether the tumor pathological origin of latent prostate cancer (lPCa) and clinical prostate cancer (cPCa) are consistent, and to verify the current clinically significant prostate cancer criteria.MethodsProstate specimens were obtained from postmortem autopsy between 2014 and 2021 and patients who went through radical prostatectomy from 2013 to 2021. The pathological characteristics and spatial distribution of the lPCa group and cPCa group were compared and analyzed through SPSS software with P < 0.05 representing statistical significant.ResultsIn lPCa group, a total of 45 tumor lesions from 24 lPCa cases were included, 54.2% of lPCa patients were ISUP ≥ 2, 12.5% had tumor volume ≥ 0.5 ml, and 16.7% had extraprostatic extension (EPE). In cPCa group, there were a total of 429 tumor lesions in 126 cases, 92.1% of cPCa patients were ISUP ≥ 2, and 82.5% had tumor volume of ≥ 0.5 ml. 36.3% had EPE. LPCa and cPCa have the same spatial distribution characteristics, and no significant difference was detected between the anterior and posterior zone. Peripheral zone tumors were significantly more common than transitional zone tumors. Tumors in apical 1/3 and middle 1/3 were significantly more common than basal 1/3.ConclusionThe malignancy of cPCa is significantly higher than that of lPCa, and the spatial distribution of cPCa and lPCa is consistent. ISUP grade 2 is not sufficient to determine clinical significance of tumor.

Clinical utility of MR/ultrasound fusion-guided biopsy in patients with lower suspicion lesions on active surveillance for low-risk prostate cancer.

The utility of Multiparametric magnetic resonance imaging (mpMRI) guided prostate biopsy among patients with prostate cancer (CaP) managed with active surveillance (AS) with low-suspicion lesions remains unsettled. We performed a retrospective analysis of 415 men with low-risk CaP managed with active surveillance. We selected men with mpMRI visible index lesions scored as 2 or 3 according to Prostate Imaging Reporting and Data System (PI-RADS) version 2. The primary outcome was detection of clinically significant prostate cancer (csCaP) was defined as Gleason grade group ≥ 2. We assessed the diagnostic accuracy of biopsy approaches using area under the receiver operator characteristic (ROC) curve and evaluated factors associated with csCaP in these patients using multivariate logistic regression. CsCaP was identified in 22 of 125 patients (17.6%) with PI-RADS 2 or 3 index lesions during surveillance prostate biopsies. These included 10 (45.5%) diagnosed by systematic biopsy alone, 9 (40.9%) by targeted alone, and 3 (13.6%) by both approaches. On multivariable analysis, the only significant variable predicting the detection of csCaP in men with low-risk imaging mpMRI characteristics was higher PSAD (OR per 0.1 unit=2.26, 95% CI 1.25-4.06, P = 0.007. A PSAD cutoff of 0.1, 0.12 and 0.15 resulted in a negative predictive value (NPV) of 90.9%, 87.1% and 86.2%, respectively. When stratified by PI-RADS score, a PSAD cutoff of 0.1, 0.12 and 0.15 resulted in NPV of 96.2%, 90.6% and 89.7% and 86.2%, 84.2% and 83.3% for detection of csCaP in PI-RADS 2 and 3 lesions, respectively. In patients with PIRDAS 2 lesions, using a PSAD of 0.1 would potentially allow 51% of patients to avoid biopsy with only a 3.8% chance of missing csCaP. In men with clinical low-risk prostate cancer on active surveillance with PI-RADS 2 and 3 lesions, there is an almost 18% risk of upgrade to csCaP. Integration of PSAD may be a useful adjunctive tool in identifying patients at highest risk for upgrade despite favorable imaging findings. In men with PIRADS 2 lesions with PSAD ≤0.12 biopsy can be avoided. For men with PIRADS 2 lesions with PSAD ≤0.15 informed decision making regarding the AS intensity should include that these patients have a low risk (>10%) of developing csCaP. In men with PIRADS 3 lesions with PSAD >0.1, shared decision making should include discussion of a >10% miss rate of csCaP.

1698P Correlation between sex steroid hormone receptors expression in prostate cancer (PCa)

PCa is well known to be an androgen-dependent disease. However, estrogens and estrogen receptors alpha and beta (ERα and ERβ) also play an important role in PCa progression. All types of receptors share similar structure and can be activated by same ligands. As so, relative amounts of all receptor types may be important in predicting overall response to therapy, including androgen deprivation. We aimed to assess possible correlations between ERα, ERβ and androgen receptor (AR) expression in clinical PCa samples.

Association between ABO blood group and unfavorable prostate cancer features after radical prostatectomy: Retrospective study of 1149 patients.

To test hypothesized associations between the ABO blood group (ABO-bg) system and the pathological features of prostate cancer (PCa). Between January 2013 and September 2019, 1173 patients underwent radical prostatectomy. Associations between ABO-bg levels and pathological features were evaluated using statistical methods. Overall, 1149 consecutive patients were evaluated using the ABO-bg system, which was represented by O-bg (42.8%) and A-bg (41.3%), followed by B-bg (11.1%) and AB-bg (4.8%). Only positive surgical margins (PSMs) was correlated with ABO-bg (Pearson correlation coefficient, r = 0.071; p = 0.017), and the risk was increased in group-O (odds ratio [OR], 1.497; 95% confidence interval, 1.149-1.950; p = 0.003) versus non-O-bg. In clinical and pathological models, O-bg was at increased risk of PSM after the adjustment for prostate-specific antigen, percentage of biopsy-positive cores, and high surgical volume (adjusted OR, 1.546; 95% confidence interval, 1.180-2.026; p = 0.002); however, the adjusted OR did not change after the adjustment for tumor load and stage as well as high surgical volume. In clinical PCa, the risk of PSM was higher in O-bg versus non-O-bg patients after the adjustment for standard predictors. Confirmatory studies are needed to confirm the association between ABO-bg and unfavorable PCa features.

FOXA1 inhibits hypoxia programs through transcriptional repression of HIF1A.

Intratumoral hypoxia is associated with castration-resistant prostate cancer (CRPC), a lethal disease. FOXA1 is an epithelial transcription factor that is down-regulated in CRPC. We have previously reported that FOXA1 loss induces epithelial-mesenchymal transition (EMT) and cell motility through elevated TGFβ signaling. However, whether FOXA1 directly regulates hypoxia pathways of CRPC tumors has not been previously studied. Here we report that FOXA1 down-regulation induces hypoxia transcriptional programs, and FOXA1 level is negatively correlated with hypoxia markers in clinical prostate cancer (PCa) samples. Mechanistically, FOXA1 directly binds to an intragenic enhancer of HIF1A to inhibit its expression, and HIF1A, in turn, is critical in mediating FOXA1 loss-induced hypoxia gene expression. Further, we identify CCL2, a chemokine ligand that modulates tumor microenvironment and promotes cancer progression, as a crucial target of the FOXA1-HIF1A axis. We found that FOXA1 loss leads to immunosuppressive macrophage infiltration and increased cell invasion, dependent on HIF1A expression. Critically, therapeutic targeting of HIF1A-CCL2 using pharmacological inhibitors abolishes FOXA1 loss-induced macrophage infiltration and PCa cell invasion. In summary, our study reveals an essential role of FOXA1 in controlling the hypoxic tumor microenvironment and establishes the HIF1A-CCL2 axis as one mechanism of FOXA1 loss-induced CRPC progression.

The 28th Annual Prostate Cancer Foundation Scientific Retreat report.

The 28th Annual Prostate Cancer Foundation (PCF) Scientific Retreat was held virtually over 4 days, on October 28-29 and November 4-5, 2021. The Annual PCF Scientific Retreat is a leading global scientific conference that focuses on first-in-field, unpublished, and high-impact basic, translational, and clinical prostate cancer research, as well as research from other fields with high probability for impacting prostate cancer research and patient care. Primary areas of research discussed at the 2021 PCF Retreat included: (i) prostate cancer disparities; (ii) prostate cancer survivorship; (iii) next-generation precision medicine; (iv) PSMA theranostics; (v) prostate cancer lineage plasticity; (vi) tumor metabolism as a cancer driver and treatment target; (vii) prostate cancer genetics and polygenic risk scores; (viii) glucocorticoid receptor biology in castration-resistant prostate cancer (CRPC);(ix) therapeutic degraders; (x) new approaches for immunotherapy in prostate cancer; (xi) novel technologies to overcome the suppressive tumor microenvironment; and (xii) real-world evidence and synthetic/virtual control arms. This article provides a summary of the presentations from the 2021 PCF Scientific Retreat. We hope that sharing this knowledge will help to improve the understanding of the current state of research and direct new advances in prostate cancer research and care.

Identification of hub genes predicting the development of prostate cancer from benign prostate hyperplasia and analyzing their clinical value in prostate cancer by bioinformatic analysis

Prostate cancer (PCa) and benign prostate hyperplasia (BPH) are commonly encountered diseases in males. Studies showed that genetic factors are responsible for the occurrences of both diseases. However, the genetic association between them is still unclear. Gene Expression Omnibus (GEO) database can help determine the differentially expressed genes (DEGs) between BPH and PCa. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were utilized to find pathways DEGs enriched. The STRING database can provide a protein–protein interaction (PPI) network, and find hub genes in PPI network. R software was used to analyze the clinical value of hub genes in PCa. Finally, the function of these hub genes was tested in different databases, clinical samples, and PCa cells. Fifteen up-regulated and forty-five down-regulated genes were found from GEO database. Seven hub genes were found in PPI network. The expression and clinical value of hub genes were analyzed by The Cancer Genome Atlas (TCGA) data. Except CXCR4, all hub genes expressed differently between tumor and normal samples. Exclude CXCR4, other hub genes have diagnostic value in predicting PCa and their mutations can cause PCa. The expression of CSRP1, MYL9 and SNAI2 changed in different tumor stage. CSRP1 and MYH11 could affect disease-free survival (DFS). Same results reflected in different databases. The expression and function of MYC, MYL9, and SNAI2, were validated in clinical samples and PCa cells. In conclusion, seven hub genes among sixty DEGs may be achievable targets for predicting which BPH patients may later develop PCa and they can influence the progression of PCa.

Quantitative and direct serum albumin detection by label-free SERS using tunable hydroxyapatite nanostructure for prostate cancer detection

With the aid of good biocompatibility and stability with hydroxyapatite (HAp) in protein separation and adsorption fields, we developed a novel extraction-isolation albumin analysis method by relying on the specific adsorption capacity of HAp, combining with surface-enhanced Raman spectroscopy (SERS) for prostate cancer screening. Two different nanostructures of HAp particles, including the HAp flower and HAp sphere, were synthesized with a hydrothermal method, and the targeted binding and extraction abilities of serum albumin of these two HAp particles were compared. By changing the morphology of the nanostructure, the albumin-adsorption capacity of HAp varied significantly. Compared with spherical HAp particles, HAp flower particles have more albumin binding sites per unit area. Thus, the HAp flower displayed the superior capacity for adsorption-release of albumin, which was further employed for clinical prostate cancer screening. Based on the superior adsorption-extraction ability of albumin of HAp flower, serum albumin was adsorbed and extracted by HAp flower from serum samples of prostate cancer patients (n = 30) and healthy volunteers (n = 30), and mixed with silver colloids to perform SERS spectral analysis. The partial least square-support vector machines (PLS-SVM) model is used to analyze the obtained serum albumin SERS spectra and establish the diagnostic model, the diagnostic accuracy was up to 95.00% for differentiating the normal volunteer from prostate patient groups. The results demonstrate that the PLS-SVM model provides superior performance in the classification of a prostate cancer diagnosis. Due to the advantages of simplicity and rapidness, the HAp flower-adsorbed-released albumin combined with SERS was expected to become a promising tool for prostate cancer detection.

Abstract 2357: Inhibition of CDK8/19 mediator kinase suppresses primary and metastatic growth of castration-resistant prostate cancer

Abstract Following androgen deprivation therapy (ADT), prostate cancers (PCa) progress to castration resistant prostate cancer (CRPC) status, independent of androgen signaling, through changes in androgen receptor (AR) or by converting to AR-negative forms. Metastatic CRPC remains incurable, and the most potent new drugs prolong survival by only a few months. There is an urgent need for novel agents against advanced CRPC. CDK8 and CDK19 are two isoforms of Mediator kinase, which regulates transcriptional reprogramming, a key process in cancer development, metastasis, and drug resistance. Bioinformatic analysis of clinical prostate cancers shows that CDK19 expression increases during PCa development and progression reaching higher levels than in any other cancers, whereas CDK8 expression increases when PCa becomes CRPC. We have investigated the effects of CDK8/19 Mediator kinase inhibition on gene expression and tumor growth in several CPRC tumor models, growing subcutaneously or in the bone, the principal cause of PCa lethality. CDK8/19 inhibition decreased androgen-stimulated expression of the most strongly androgen-regulated genes, including PSA, in androgen-responsive PCa in vitro and in vivo. CRISPR knockout of both CDK8 and CDK19 in 22Rv1 CRPC cells that express both full-length AR and its androgen-independent V7 variant, had little effect on the tumor growth in intact male mice but strongly suppressed tumor growth in castrated animals. Moreover, re-expression of CDK19 but not of its kinase-dead mutant partially restored tumor growth in castrated mice. Similarly, SNX631, a selective CDK8/19 inhibitor, had little effect on 22Rv1 growth in intact mice but strongly suppressed the growth of these cells (but not of their knockout derivative) in castrated mice. Prolonged (up to 300 days) treatment with SNX631 induced tumor shrinkage and disappearance in a subset of 22Rv1 tumors grown in castrated animals. Transcriptomic analysis revealed that CDK8/19 inhibition or knockout suppressed castration-induced transcriptional reprogramming in tumor cells and affected stromal gene expression. SNX631 also inhibited the growth of a CRPC PDX derived from a PCa patient who failed casodex, abiraterone, and docetaxel, in castrated mice. SNX631 also significantly inhibited in vivo growth of AR-negative PC3 cells both in the flank and in the bone, the principal metastatic site of PCa. These results warrant the development of CDK8/19 inhibitors for the presently incurable metastatic CRPC. Funding acknowledgement: This research was funded by NIH grant R44CA203184 (M.C., I.R., M.L., Y.S.) Citation Format: Jing Li, Thomas Hilimire, Chen Cheng, Eugenia V. Broude, Yueying Liu, Michael B. Lilly, Yusuke Shiozawa, George Wilding, Igor B. Roninson, Mengqian Chen. Inhibition of CDK8/19 mediator kinase suppresses primary and metastatic growth of castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2357.

Developing a Multimodal Model for Detecting Higher-Grade Prostate Cancer Using Biomarkers and Risk Factors.

A technique to predict crucial clinical prostate cancer (PC) is desperately required to prevent diagnostic errors and overdiagnosis. To create a multimodal model that incorporates long-established messenger RNA (mRNA) indicators and conventional risk variables for identifying individuals with severe PC on prostatic biopsies. Urinary has gathered for mRNA analysis following a DRE and before a prostatic examination in two prospective multimodal investigations. A first group (n = 489) generated the multimodal risk score, which was then medically verified in a second group (n = 283). The reverse transcription qualitative polymerase chain reaction determined the mRNA phase. Logistic regression was applied to predict risk in patients and incorporate health risks. The area under the curve (AUC) was used to compare models, and clinical efficacy was assessed by using a DCA. The amounts of sixth homeobox clustering and first distal-less homeobox mRNA have been strongly predictive of high-grade PC detection. In the control subjects, the multimodal method achieved a total AUC of 0.90, with the most important aspects being the messenger riboneuclic acid features' PSA densities and previous cancer-negative tests as a nonsignificant design ability to contribute to PSA, aging, and background. An AUC of 0.86 was observed for one more model that added DRE as an extra risk component. Two methods were satisfactorily verified without any significant changes within the area under the curve in the validation group. DCA showed a massive net advantage and the highest decrease in inappropriate costs.