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TP53 loss-of-function is commonly found in aggressive prostate cancer. However, a highly-efficient therapy for this tumor subtype is still lacking. In this study, we investigated the relationship between TP53 mutation status and autophagy in prostate cancer and assessed the efficacy of autophagy inhibitors on TP53-deficient tumors.We first evaluated the expression patterns of p53 and autophagy-related proteins, namely LC3B, ULK1 and BECLIN1, as well as their relationship in treatment-naïve and castration-resistant prostate cancer specimens through immunohistochemistry. Subsequently, we generated a Trp53-deleted genetically-engineered mouse model, established prostate tumor organoid lines from the mice and assessed the efficacy of autophagy inhibitors in overcoming Enzalutamide resistance in the tumor organoid model. We also investigated the impact of TP53 re-expression in modulating responses to autophagy inhibitors using LNCaP cell line, which harbored a TP53 missense mutation. Lastly, we attempted to identify potential autophagy-related genes that were crucial for TP53-deficient tumor maintenance.TP53 loss-of-function was associated with increased levels of autophagy-related proteins in aggressive prostate cancers and Trp53-deleted genetically-engineered mouse-derived tumors. Moreover, the generated androgen receptor-independent tumor organoids were highly vulnerable to autophagy inhibition. Upon TP53 re-expression, not only did the surviving LNCaP cells demonstrate resistance, but they also showed growth advantage in response to autophagy inhibition. Lastly, PEX14, an important peroxisomal regulator was differentially upregulated in aggressive tumors with TP53 loss-of-function mutations, thus implying the importance of peroxisome turnover in this tumor subtype.Our results support the potential use of autophagy inhibitors in prostate cancers that contain TP53 loss-of-function mutations.

Prostate cancer (PCa) is the most frequent cancer in men. Developing new treatment methods for CRPC will be a significant challenge in the clinical treatment of PCa. In conclusion, the results of this study show that NRF2 is downregulated in untreated PCa samples compared to normal PCa samples; however, it was upregulated in mCRPC samples compared to HSPC samples. These results demonstrated that NRF2 may serve as a tumor suppressor in tumorigenesis but promote PCa androgen-independent transferring after ADT treatment. Bioinformatics analysis showed that NRF2 was related to multiple signaling, such as the AGE-RAGE pathway, MAPK pathway, NF-kappa B signaling, PI3K-Akt signaling pathway, and VEGF signaling pathway. Moreover, we revealed that the NRF2 inhibitor significantly inhibited tumorigenicity of CRPC cells in vitro. Of note, combination of the NRF2 inhibitor and autophagy inhibitor had a more significantly suppressive role than either ML385 or CQ, indicating that combination of CQ (autophagy inhibitor) and ML385 (NRF2 inhibitor) is a potential treatment of CRPC. Finally, we conformed that high levels of autophagy regulators LC3B, ULK1, and beclin1 significantly correlated to longer PSA recurrence-free survival time. We think that this study could provide more evidence to confirm that NRF2 is a crucial regulator and targeting NRF2 and autophagy is a potential therapy option for CRPC.

Most prostate cancer (PCa)-related deaths are caused by progression to bone metastasis. Recently, the importance of extracellular vesicles (EVs) in pre-metastatic niche formation has been reported. However, whether and how tumor-derived EVs interact with bone marrow macrophages (BMMs) to release EV-delivered microRNAs to promote osteolysis and induce pre-metastatic niche formation for PCa bone metastasis remain unclear. Our in vitro and in vivo functional and mechanistic assays revealed that EV-mediated release of miR-378a-3p from tumor cells was upregulated in bone-metastatic PCa, maintaining low intracellular miR-378a-3p concentration to promote proliferation and MAOA-mediated epithelial-to-mesenchymal transition. Moreover, miR-378a-3p enrichment in tumor-derived EVs was induced by hnRNPA2B1 (a transfer chaperone) overexpression. After tumor-derived EVs were taken in by BMMs, enriched miR-378a-3p promoted osteolytic progression by inhibiting Dyrk1a to improve Nfatc1 (an osteolysis-related transcription factor) nuclear translocation, to activate the expression of downstream target gene Angptl2. As a feedback, increased Angptl2 secretion into the tumor environment promoted PCa progression. In conclusion, tumor-derived miR-378a-3p-containing EVs play a significant role in PCa bone metastasis by activating the Dyrk1a/Nfatc1/Angptl2 axis in BMMs to induce osteolytic progression, making miR-378a-3p a potential predictor of metastatic PCa. Reducing the release of miR-378a-3p-containing EVs or inhibiting the recruitment of miR-378a-3p into EVs can be a therapeutic strategy against PCa metastasis.

To explore the diagnostic value of the Prostate Imaging–Reporting and Data System version 2.1 (PI-RADS v2.1) for clinically significant prostate cancer (CSPCa) in patients with a history of transurethral resection of the prostate (TURP), we conducted a retrospective study of 102 patients who underwent systematic prostate biopsies with TURP history. ROC analyses and logistic regression analyses were performed to demonstrate the diagnostic value of PI-RADS v2.1 and other clinical characteristics, including PSA and free/total PSA (F/T PSA). Of 102 patients, 43 were diagnosed with CSPCa. In ROC analysis, PSA, F/T PSA, and PI-RADS v2.1 demonstrated significant diagnostic value in detecting CSPCa in our cohort (AUC 0.710 (95%CI 0.608–0.812), AUC 0.768 (95%CI 0.676–0.860), AUC 0.777 (95%CI 0.688–0.867), respectively). Further, PI-RADS v2.1 scores of the peripheral and transitional zones were analyzed separately. In ROC analysis, PI-RADS v2.1 remained valuable in identifying peripheral-zone CSPCa (AUC 0.780 (95%CI 0.665–0.854; p < 0.001)) while having limited capability in distinguishing transitional zone lesions (AUC 0.533 (95%CI 0.410–0.557; p = 0.594)). PSA and F/T PSA retain significant diagnostic value for CSPCa in patients with TURP history. PI-RADS v2.1 is reliable for detecting peripheral-zone CSPCa but has limited diagnostic value when assessing transitional zone lesions.

The study aimed to investigate the efficacy and safety outcomes in hormone-sensitive oligometastatic prostate cancer (OMPC) patients treated with docetaxel-based neoadjuvant chemohormonal therapy (NCHT) prior to radical prostatectomy (RP) compared with direct RP and standard androgen deprivation therapy (ADT) alone using propensity score match (PSM) analysis.A single-center, prospective, three-arm study was conducted with hormone-sensitive OMPC patients. Eligible patients (N = 130) were divided into three groups-NCHT, RP, and standard treatment (ST)-and received their respective treatments. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were pathological response rate, radiographic progression-free survival (rPFS), and overall survival (OS). Further, propensity scores were calculated and group-wise comparisons were carried out: NCHT versus RP, ST versus RP, and ST versus NCHT.After PSM, in the NCHT group, two patients (11.76%) and four patients (23.52%) had complete and partial pathological responses, respectively. Univariate and multivariate Cox regression analysis showed that PFS and rPFS were significantly higher in the NCHT group. For NCHT versus RP, the PFS hazard ratio (HR) = 0.11 (95% confidence interval [CI], 0.02-0.51; P = .004) and HR = 0.016 (95% CI, 0.0015-0.17; P.001); the rPFS HR = 0.088 (95% CI, 0.011-0.71; P = .023) and HR = 0.03 (95% CI, 0.0025-0.36; P = .006). Further, the median OS of the ST group was 44.6 months for ST versus RP, and it was 49.3 months for ST versus NCHT; it was not reached in either the NCHT or RP group. Furthermore, 17.65% and 47.06% patients had positive surgical margins in the NCHT and RP groups, respectively, and no therapy-related deaths were observed during the study period.PSM analysis revealed NCHT before RP in OMPC patients has potential therapeutic benefits with acceptable toxicities and lower incidence of postoperative positive surgical margins.

We sought to explore the genomic features of bone-only metastasis, hepatic metastasis and pulmonary metastasis without liver involvement in prostate cancer using targeted next-generation sequencing.A hybridization capture-based next-generation sequencing was performed to detected genomic alterations in 50 genes, including androgen receptor, DNA damage response and other clinical relevant drivers.We successfully sequenced circulating tumor DNA from 109 blood samples and 29 metastatic tissue samples from 129 patients with metastatic castration-resistant prostate cancer (metastatic castration-resistant prostate cancer). We observed distinct genomic profiles of metastatic castration-resistant prostate cancer across various metastatic sites. High prevalence ofThrough genomic profiling of prostate cancer across various metastatic sites, we identified an extremely low frequency of

To explore the genomic profiles of Chinese patients with castration sensitive prostate cancer and those with metastatic castration resistant prostate cancer via germline and circulating tumor DNA sequencing.A hybridization capture based next-generation sequencing assay was used to identify germline and somatic alterations in 50 genes including androgen receptor pathway genes, DNA damage repair pathway genes,We successfully sequenced DNA from 396 blood samples and 32 matched tumor tissue samples from 396 patients. We observed a similar frequency of deleterious germline alterations between patients with castration sensitive prostate cancer and metastatic castration resistant prostate cancer (8.9% vs 9.8%, p0.05). There was a high consistency (90.9%) between metastatic tumor tissue and matched circulating tumor DNA. Among patients who were circulating tumor DNA positive we observed significantly higher alteration frequencies ofThrough genomic profiling of prostate cancer across clinical states we identified a similar frequency of deleterious germline alterations between patients with castration sensitive prostate cancer and metastatic castration resistant prostate cancer. We explored the genomic diversity of androgen receptor and DNA damage repair pathway genes between patients with metastatic castration sensitive prostate cancer and metastatic castration resistant prostate cancer. Higher alteration frequencies of

Purpose: To identify extracellular vesicle (EV)-delivered microRNAs in the patient's serum as indicators for bone-metastatic prostate cancer. Methods: First, the profiling change of serum EV-delivered miRNAs in patients with either benign prostatic hyperplasia (BPH), non-bone metastatic prostate cancer or bone-metastatic prostate cancer was detected by microRNA deep sequencing assay and microRNA-chip array assay, respectively. Second, the candidates were further confirmed using TaqMan microRNA assay in two independent validation cohorts of total 176 patients with either BPH, non-bone metastatic prostate cancer or bone metastatic prostate cancer to seek the most valuable microRNA(s). Results: Through microRNA deep sequencing and microRNA-chip array, we found 4 prospective EV-delivered miRNAs including miR-181a-5p with significantly upregulated expression in bone metastatic groups than in non-bone metastatic prostate cancer groups (p < 0.05). In the validation cohorts, logistic regression analysis was performed to evaluate the diagnostic association of candidates with bone metastasis, which indicated that miR-181a-5p was significantly associated with bone metastatic prostate cancer. Furthermore, accuracy estimate of each candidate for the diagnosis of bone metastatic prostate cancer was quantified using the area under the receiver-operating characteristic curve (AUC), which identified miR-181a-5p as the best biomarker with the AUCs of 85.6% for diagnosis of prostate cancer and 73.8% for diagnosis of bone metastatic prostate cancer. Conclusion: EV-delivered miR-181a-5p from patient's serum is a promising diagnostic biomarker for bone metastatic prostate cancer.

Advances in bioimaging technologies have led to unprecedented findings of novel biological processes at the nanoscale. However, there remains an ever-lasting demand for the improvement of spatiotemporal resolution, multiplexity, and smart responsiveness of bioimaging in living systems. In recent decades, self-assembled DNA nanostructures with highly programmable shape, nanometer addressability, and structural responsiveness have shown great promise in developing nanoscale probes and labels for high-performance bioimaging. Here, we briefly review the recent progress in structural DNA nanotechnology and the development of DNA frameworks, and summarize the bioimaging strategies empowered by DNA nanotechnology. We highlight the advantages of DNA nanostructures in overcoming the bottlenecks in bioimaging and discuss the challenges and opportunities in this field.

Intratumoral heterogeneity remains as a major challenge in the treatment resistance of prostate cancer. Understanding the mechanism of prostate cancer heterogeneity is essential for developing effective therapies. In this study, we reported the heterogeneous activation of Wnt/β-catenin signaling in prostate cancer. We developed a Wnt/β-catenin signaling reporting system to directly characterize the differences between Wnt/β-catenin signaling active (GFP+) and inactive (GFP-) cells. Compared to GFP- cells, GFP+ cells demonstrated cancer stem cell properties with higher colony formation efficiency, slower cell cycle, higher resistance to docetaxel and higher expression of cancer stem cell markers. In addition, we found that Wnt/β-catenin signaling is negatively correlated with H3K27me3 levels. Further studies demonstrated that Wnt/β-catenin signaling affected H3K27me3 levels by regulating the expression of KDM6A, one of the H3K27me3 demethylases. H3K27me3 suppressed Wnt/β-catenin signaling by directly silencing LEF1 promoter. Together, our studies suggest that Wnt/β-catenin signaling makes a major contribution to prostate cancer heterogeneity and targeting both Wnt/β-catenin signaling active and inactive populations is essential for developing more effective therapies.

Background Prostate cancer (PCa) is one of the most common cancers in men, but its metabolic characteristics during tumor progression are still far from being fully understood. Methods The metabolic profiles of matched tissue, serum and urine samples from the same patients were analyzed using a 1H NMR-based metabolomics approach. We identified several important metabolites that significantly altered at different stages of PCa, including benign prostatic hyperplasia (BPH), early PCa (EPC), advanced PCa (APC), metastatic PCa (MPC) and castration-resistant PCa (CRPC). Metabolic correlation networks among tissue, serum and urine samples were examined using Pearson’s correlation. Results The changes in metabolic phenotypes during the progression of PCa were more noticeable in tissue samples when compared with serum and urine samples. Herein we identified a series of important metabolic disturbances, including decreased trends of citrate, creatinine, acetate, leucine, valine, glycine, lysine, histidine, glutamine and choline as well as increased trends of uridine and formate. These metabolites are mainly implicated in energy metabolism, amino acid metabolism, choline and fatty acid metabolism as well as uridine metabolism. We also found that energy metabolism in tumor tissues was positively associated with amino acid metabolism in serum and urine. Additionally, CRPC patients had a peculiar metabolic phenotype, especially decreased amino acid metabolism in serum. Conclusions The present study characterizes metabolic disturbances in both tissue and biofluid samples during PCa progression and provides potential diagnostic biomarkers and therapeutic targets for PCa.

Prostate cancer (PCa) is the second most prevalent cancer in males worldwide, yet detecting PCa and its metastases remains a major challenging task in clinical research setups. The present study aimed to characterize the metabolic changes underlying the PCa progression and investigate the efficacy of related metabolic panels for an accurate PCa assessment.In the present study, 75 PCa subjects, 62 PCa patients with bone metastasis (PCaB), and 50 benign prostatic hyperplasia (BPH) patients were enrolled, and we performed a cross-sectional metabolomics analysis of serum samples collected from these subjects using aMultivariate analysis revealed that BPH, PCa, and PCaB groups showed distinct metabolic divisions, while univariate statistics integrated with variable importance in the projection (VIP) scores identified a differential metabolite series, which included energy, amino acid, and ketone body metabolism. Herein, we identified a series of characteristic serum metabolic changes, including decreased trends of 3-HB and acetone as well as elevated trends of alanine in PCa patients compared with BPH subjects, while increased levels of 3-HB and acetone as well as decreased levels of alanine in PCaB patients compared with PCa. Additionally, our results also revealed the metabolic panels of discriminant metabolites coupled with the clinical parameters (age and body mass index) for discrimination between PCa and BPH, PCaB and BPH, PCaB and PCa achieved the AUC values of 0.828, 0.917, and 0.872, respectively.Overall, our study gave successful discrimination of BPH, PCa and PCaB, and we characterized the potential metabolic alterations involved in the PCa progression and its metastases, including 3-HB, acetone and alanine. The defined biomarker panels could be employed to aid in the diagnosis and classification of PCa in clinical practice.

Prostate cancer (PCa) incidence and mortality have rapidly increased in China. Notably, unique epidemiological characteristics of PCa are found in the Chinese PCa population, including a low but rising incidence and an inferior but improving disease prognosis. Consequently, the current treatment landscape of PCa in China demonstrates distinct features. Establishing a more thorough understanding of the characteristics of Chinese patients may help provide novel insights into potential treatment strategies for PCa patients. Herein, we review the epidemiological status and differences in treatment modalities of Chinese PCa patients. In addition, we discuss the underlying socioeconomic and biological factors that contribute to such diversity and further propose directions for future efforts in optimizing the PCa treatment in China.

Objective: To evaluate the real-world effectiveness and gene predictive analysis of olaparib in Chinese patients with metastatic castration-resistant prostate cancer (mCRPC) .Methods: A multicenter, retrospective, real-world study was conducted by involving Chinese patients with mCRPC from December 2017 to June 2021. Homologous Recombination repair (HRR)gene mutation (HRRm) status was identified using targeted next-generation sequencing (NGS). The primary endpoint includes prostate-specific antigen (PSA) response rate (PSA50). Secondary end points include PSA progression-free survival (PSA-PFS), exploratory endpoints include PSA50, and PSA-PFS in HRRm-negative patients with variants of unknown significance (VUS). Survival rates were analyzed using Kaplan–Meier (KM) plot.Results: A total of 39 eligible patients with a median age of 65 (interquartile range [IQR]: 59.5-69.5) years were included in the study. Overall, 40% (12/30) of the patients with mCRPC achieved PSA50 and the median PSA-PFS was 3.1 months (95% Confidence interval [CI]: 2.4-7). Furthermore, higher PSA50 rate and longer PSA-PFS were observed in HRRm-positive patients (PSA50: 50% [7/14]; median PSA-PFS: 5.3 months, 95% CI: 3.73–10). Among the HRRm-positive patients, those harboring the BRCA2 aberrations experienced best clinical efficacy (PSA50: 55.5% [5/9] and median PSA-PFS [95% CI]: 9.5 months [4.3, NA]). Clinical benefit was also observed in HRRm-negative patients (PSA50: 31.3% [5/16]; median PSA-PFS [95% CI]:2.05 months [1.5,8]), wherein most patients with a PSA50 response were carrying VUS mutations (PSA50: 50% [4/8]; median PSA-PFS [95% CI]: 2.75 months [1.27, NA]). In one patients with mutation in the ATR gene, the PSA level decreased by 62%. Conclusion: Olaparib improved PSA response and prolonged PSA-PFS in Chinese mCRPC patients especially in those carrying HRR mutation. Among the HRR genes, patients with BRCA2 mutation showed the best clinical benefit. Besides, some patients carrying HRR VUS alternations and other DNA damage response (DDR) gene mutations also showed response to olaparib treatment, indicating that the clinical benefits observed in HRR negative group were driven by VUS and other DDR gene mutation. However, this should be further explored in the future, and more molecular functional studies are needed to reclassify VUS mutations for better clinical treatment decision-making and management of mCRPC.

DNA aptamers and framework DNA nanostructures are emerging DNA materials with many appealing biological applications including biosensing, bioimaging, drug delivery, and so forth. When placed in physiological fluids, they inevitably encounter biomolecules (majorly proteins) and form complexes that largely affect their biological fate. Nevertheless, little is known regarding the quantitative profile of proteins that adsorb to DNA aptamers and DNA nanostructures in biological environments, and there are no potent strategies to regulate protein profiles. Herein, we performed a proteomic analysis to profile proteins that bind to DNA aptamers (Sgc8c and SYLC3) and nanostructures (a tetrahedral DNA nanostructure and a DNA origami rod) in human serum using liquid chromatography-mass spectrometry (LC-MS). Dozens to hundreds of proteins were identified with each DNA material exhibiting highly distinctive profiles. It was also revealed that the origin of serum (from healthy donor vs from prostate cancer patients) causes significant differences in profiles of bound proteins. Furthermore, we demonstrated that the protein profile may be regulated by tethering a layer of single-stranded DNA (polythymine) onto the DNA origami rod to alleviate the adsorption of complement-associated proteins, which significantly reduced its sequestration by macrophages. Taken together, this study has provided qualitative and quantitative proteomic profiles regarding serum proteins that adsorb to various DNA materials and have demonstrated that the composition of interacted proteins may be regulated toward better biological performances.

Myeloid-derived suppressor cells (MDSC) can suppress immunity and promote tumorigenesis, and their abundance is associated with poor prognosis. In this study, we show that SUMO1/sentrin-specific peptidase 1 (SENP1) regulates the development and function of MDSC. SENP1 deficiency in myeloid cells promoted MDSC expansion in bone marrow, spleen, and other organs. Senp1−/− MDSC showed stronger immunosuppressive activity than Senp1+/+ MDSC; we observed no defects in the differentiation of myeloid precursor cell in Senp1−/− mice. Mechanistically, SENP1-mediated regulation of MDSC was dependent on STAT3 signaling. We identified CD45 as a specific STAT3 phosphatase in MDSC. CD45 was SUMOylated in MDSC and SENP1 could deconjugate SUMOylated CD45. In Senp1−/− MDSC, CD45 was highly SUMOylated, which reduced its phosphatase activity toward STAT3, leading to STAT3-mediated MDSC development and function. These results reveal a suppressive function of SENP1 in modulating MDSC expansion and function via CD45–STAT3 signaling axis. Significance: These findings show that increased SUMOylation of CD45 via loss of SENP1 suppresses CD45-mediated dephosphorylation of STAT3, which promotes MDSC development and function, leading to tumorigenesis.

Jiahua Pan,1,* Xiaoguang Shao,1,* Yinjie Zhu,1,* Baijun Dong,1 Yanqing Wang,1 Xiaonan Kang,2 Na Chen,3 Zhenyi Chen,3 Shupeng Liu,3 Wei Xue1 1Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People’s Republic of China; 2Department of Biobank, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People’s Republic of China; 3Shanghai Institute for Advanced Communication and Data Science, Key Laboratory of Specialty Fiber Optics and Optical Access Networks, School of Communication and Information Engineering, Shanghai University, Shanghai, People’s Republic of China *These authors contributed equally to this work Objective: The objective of this study was to evaluate the performance of surface-enhanced Raman spectroscopy (SERS) in the prediction of early biochemical recurrence after radical prostatectomy (RP).Patients and methods: We synthesized monodisperse gold nanoparticles as SERS-enhanced substrates and analyzed preoperative plasma samples of patients who underwent RP. The roles of clinical risk model (Cancer of the Prostate Risk Assessment [CAPRA] score) and distinctive SERS spectra on prediction of early biochemical recurrence were evaluated. The principal component analysis and linear discriminant analysis (PCA-LDA) were used to manage the spectral data and develop diagnostic algorithm.Results: A total of 306 preoperative plasma Raman spectra from 102 patients were collected. SERS spectrum from those who developed early biochemical recurrence were compared to those who remained biochemical recurrence-free. The SERS detected more abundant circulating free nucleic acid bases in biochemical recurrence population, presenting significant stronger intensities at SERS spectral bands 725 and 1,328 cm-1. The addition of Raman spectral peak 1,328 cm-1 to CAPRA postsurgical (CAPRA-S) score significantly improved the predictive power of logistic regression model compared to simple CAPRA score (P

IMPORTANCE: Focal therapy of prostate cancer must balance the oncologic outcome and functional outcome. High-frequency irreversible electroporation (H-FIRE) can destroy cancer cells while selectively preserving surrounding nerves and blood vessels, but no clinical trials have been conducted, to our knowledge. OBJECTIVE: To evaluate the efficacy and safety of H-FIRE in the treatment of localized prostate cancer (PCa). DESIGN, SETTING, AND PARTICIPANTS: This was a single-group, objective performance criteria, nonrandomized controlled trial. Recruitment began on May 2, 2018, and ended March 27, 2019. The follow-up duration was 6 months. This was a multicenter trial conducted at 4 tertiary teaching hospitals in China. Patients with low or intermediate risk of biochemical recurrence of localized and locally advanced PCa were eligible. Key inclusion criteria were serum prostate-specific antigen (PSA) level less than 20 ng/mL, clinical stage of T2c or less, and Gleason score of 7 or less. Data were analyzed from January 20 to February 20, 2021. INTERVENTION: H-FIRE ablation of all lesions identified with biopsy. MAIN OUTCOMES AND MEASURES: The primary end point was 6-month clinically significant PCa (csPCa), which was defined as any biopsy core with Gleason score of greater than or equal to 7, or Gleason score of 6 plus maximum cancer core length of greater than 3 mm or an increase from the original cancer burden. Secondary outcomes were calculated in patients who actually received H-FIRE treatment. RESULTS: A total of 117 patients (median [IQR] age, 67 [62-73] years) were recruited from 4 centers, and 109 patients (27 [24.8%] low risk and 82 [75.2%] intermediate risk) actually received H-FIRE. Median (IQR) PSA level was 9.0 (6.0-12.7) ng/mL. Among the 100 patients who underwent biopsy at 6 months, the 6-month csPCa rate was 6.0% (95% CI, 2.2%-12.6%; P

Background To evaluate the efficacy and safety of abiraterone acetate (AA) plus prednisone compared with prednisone alone in Asian patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), and to identify predictive factors. Methods We reviewed the medical records of 60 patients with chemotherapy-naive mCRPC at Renji Hospital who were treated with AA plus prednisone (n = 43) or prednisone alone (n = 17). All patients were assessed for prostate-specific antigen (PSA) response, PSA progression-free survival (PSA PFS), radiographic progression-free survival (rPFS), and overall survival (OS). The ability of several parameters to predict PSA PFS, rPFS, and OS was studied. Results The median follow-up time was 14.0 months (range 7.0–18.5 months), at which time 19 death events had been reported: 11 in the AA + prednisone group and 8 in the prednisone group. The AA + prednisone group had significantly longer median PSA PFS (10.3 vs 3.0 months, P

We aimed to explore the association between genomic status and clinical outcome of platinum-based chemotherapy among patients with metastatic castration-resistant prostate cancer (mCRPC).We conducted a retrospective study of 55 patients with mCRPC who received platinum-based chemotherapy after the progression to docetaxel chemotherapy and underwent genomic profiling of 14 homologous recombination (HR) pathway genes. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method.Of 55 patients, 23 harbored genomic defects in HR pathway genes. Median prostate specific antigen (PSA)-PFS for the HR defect group was 6.7 months compared with 2.6 months for the no HR defect group (p=0.001). The patients harboring somatic HR defect displayed shorter PSA-PFS than those harboring germline HR defect (4.5 months vs not available; p=0.066). The PSA50 (patients who survived for 12 weeks and had a PSA decline over 50% from baseline) response rate displayed higher in patients harboringThe patients with mCRPC harboring alterations in different HR genes displayed distinct response to platinum-based chemotherapy. Patients with mCRPC harboring genomic defects in crucial HR genes either in the germline or somatic, especially

Human hexokinase 2 is an essential regulator of glycolysis that couples metabolic and proliferative activities in cancer cells. The binding of hexokinase 2 to the outer membrane of mitochondria is critical for its oncogenic activity. However, the regulation of hexokinase 2 binding to mitochondria remains unclear. Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K492. SUMO-specific protease SENP1 mediates the de-SUMOylation of hexokinase 2. SUMO-defective hexokinase 2 preferably binds to mitochondria and enhances both glucose consumption and lactate production and decreases mitochondrial respiration in parallel. This metabolic reprogramming supports prostate cancer cell proliferation and protects cells from chemotherapy-induced cell apoptosis. Moreover, we demonstrate an inverse relationship between SENP1-hexokinase 2 axis and chemotherapy response in prostate cancer samples. Our data provide evidence for a previously uncovered posttranslational modification of hexokinase 2 in cancer cells, suggesting a potentially actionable strategy for preventing chemotherapy resistance in prostate cancer., The oncogenic activity of Hexokinase 2, the first rate-limiting enzyme of glycolysis, requires its mitochondrial localization. Here, the authors show that SUMOylation of hexokinase 2 disrupts its binding to mitochondria and protects cells from tumorigenesis in prostate cancer.

The HOX genes are a group of highly conserved Homeobox-containing genes that control the body plan organization during development. However, their contributions to tumorigenesis and tumor progression remain uncertain and controversial. Here we provided evidence of tumor-suppressive activity of HOXD13 in prostate cancer. HOXD13 depletion contributes to more aggressiveness of prostate cancer cells in vitro and in vivo. These effects were corroborated in a metastatic mice model, where we observed more bone metastatic lesions formed by prostate cancer cells with HOXD13 ablation. Mechanistically, HOXD13 prevents BMP4-induced epithelial-mesenchymal transition (EMT) by inhibiting mothers against decapentaplegic homolog 1 (SMAD1) transcription. Both bioinformation and our tissue microarray cohort data show that HOXD13 expression inversely correlated in advanced prostate cancer patient specimens. Our findings establish HOXD13 as a negative regulator of prostate cancer progression and metastasis by preventing BMP4/SMAD1 signaling, and potentially suggest new strategies for targeting metastatic prostate cancer.

Neuroendocrine prostate cancer is one of the most aggressive subtypes of prostate tumor. Although much progress has been made in understanding the development of neuroendocrine prostate cancer, the cellular architecture associated with neuroendocrine differentiation in human prostate cancer remain incompletely understood. Here, we use single-cell RNA sequencing to profile the transcriptomes of 21,292 cells from needle biopsies of 6 castration-resistant prostate cancers. Our analyses reveal that all neuroendocrine tumor cells display a luminal-like epithelial phenotype. In particular, lineage trajectory analysis suggests that focal neuroendocrine differentiation exclusively originate from luminal-like malignant cells rather than basal compartment. Further tissue microarray analysis validates the generality of the luminal phenotype of neuroendocrine cells. Moreover, we uncover neuroendocrine differentiation-associated gene signatures that may help us to further explore other intrinsic molecular mechanisms deriving neuroendocrine prostate cancer. In summary, our single-cell study provides direct evidence into the cellular states underlying neuroendocrine transdifferentiation in human prostate cancer., Using single-cell RNA sequencing, Dong, Miao, Wang et al. profile the transcriptomes of 21,292 cells from biopsies of 6 castration-resistant prostate cancers. They find that all neuroendocrine tumor cells display a luminal-like epithelial phenotype, providing insights into the cellular states underlying neuroendocrine transdifferentiation in human prostate cancer.

Casein kinases are a large family of intracellular serine/threonine kinases that control a variety of cellular signaling functions. Here we report that a member of casein kinase 1 family, casein kinase 1G2, CSNK1G2, binds and inhibits the activation of receptor-interacting kinase 3, RIP3, thereby attenuating RIP3-mediated necroptosis. The binding of CSNK1G2 to RIP3 is triggered by auto-phosphorylation at serine 211/threonine 215 sites in its C-terminal domain. CSNK1G2-knockout mice showed significantly enhanced necroptosis response and pre-maturing aging of their testis, a phenotype that was rescued by either double knockout of the RIP3 gene or feeding the animal with a RIP1 kinase inhibitor-containing diet. Moreover, CSNK1G2 is also co-expressed with RIP3 in human testis, and the necroptosis activation marker phospho-MLKL was observed in the testis of old (>80) but not young men, indicating that the testis-aging program carried out by the RIP3-mediated and CSNK1G2-attenuated necroptosis is evolutionarily conserved between mice and men.

Objectives Reprogramming of cellular metabolism is profoundly implicated in tumorigenesis and can be exploited to cancer treatment. Cancer cells are known for their propensity to use glucose‐dependent glycolytic pathway instead of mitochondrial oxidative phosphorylation for energy generation even in the presence of oxygen, a phenomenon known as Warburg effect. The type II beta regulatory subunit of protein kinase A (PKA), PRKAR2B, is highly expressed in castration‐resistant prostate cancer (CRPC) and contributes to tumour growth and metastasis. However, whether PRKAR2B regulates glucose metabolism in prostate cancer remains largely unknown. Materials and methods Loss‐of‐function and gain‐of‐function studies were used to investigate the regulatory role of PRKAR2B in aerobic glycolysis. Real‐time qPCR, Western blotting, luciferase reporter assay and chromatin immunoprecipitation were employed to determine the underlying mechanisms. Results PRKAR2B was sufficient to enhance the Warburg effect as demonstrated by glucose consumption, lactate production and extracellular acidification rate. Mechanistically, loss‐of‐function and gain‐of‐function studies showed that PRKAR2B was critically involved in the tumour growth of prostate cancer. PRKAR2B was able to increase the expression level of hypoxia‐inducible factor 1α (HIF‐1α), which is a key mediator of the Warburg effect. Moreover, we uncovered that HIF‐1α is a key transcription factor responsible for inducing PRKAR2B expression in prostate cancer. Importantly, inhibition of glycolysis by the glycolytic inhibitor 2‐deoxy‐d‐glucose (2‐DG) or replacement of glucose in the culture medium with galactose (which has a much lower rate than glucose entry into glycolysis) largely compromised PRKAR2B‐mediated tumour‐promoting effect. Similar phenomenon was noticed by genetic silencing of HIF‐1α. Conclusions Our study identified that PRKAR2B‐HIF‐1α loop enhances the Warburg effect to enable growth advantage in prostate cancer., Proposed model illustrates that PRKAR2B‐HIF1α loop promotes aerobic glycolysis and tumour growth in prostate cancer. On the one hand, HIF1α is a key transcription factor responsible for inducing PRKAR2B expression in prostate cancer. On the other hand, PRKAR2B was able to increase the expression level of HIF1α.

The purpose of this study was to prospectively evaluate the distribution of PSMA-targeted, PET-avid lesions in prostate cancer (PCa) patients with biochemical recurrence in a Chinese cohort. The relationships between PSA levels, disease-free time after prostatectomy, and

Background: This study aimed to describe the aberrations of DNA damage repair genes and other important driving genes in Chinese patients with metastatic castration-resistant prostate cancer (mCRPC) using circulating tumor (ctDNA) sequencing and to evaluate the associations between the clinical outcomes of multiple therapies and key genomic alterations in mCRPC, especially DNA damage repair genes. Patients and Methods: A total of 292 Chinese patients with mCRPC enrolled from 8 centers. Multigene targeted sequencing was performed on 306 ctDNA samples and 23 matched tumor biopsies. The frequency of genomic alterations were compared with the Stand Up to Cancer–Prostate Cancer Foundation (SU2C-PCF) cohort. The Kaplan-Meier method was used to evaluate progression-free survival (PFS) following standard systemic treatments for mCRPC. Cox regression analyses were performed to determine prognostic factors associated with PFS resulting from treatments for mCRPC. Results: In total, 33 of 36 (91.7%) mutations were found consistently between ctDNA and paired biopsy samples. The most common recurrent genomic alterations were found in AR (34.6%), TP53 (19.5%), CDK12 (15.4%), BRCA2 (13%), and RB1 (5.8%). The frequency of CDK12 alterations (15.4%) in our cohort was significantly higher than that in Western populations (5%–7%). AR amplification and TP53 and/or RB1 alterations were associated with resistance to abiraterone or docetaxel. Patients with a CDK12 defect showed rapid disease progression after abiraterone treatment. However, the clinical outcome after docetaxel treatment was similar between patients with and without CDK12 defects. In multivariate Cox regression analysis, a CDK12 defect was significantly associated with inferior PFS after abiraterone treatment. Patients with a BRCA2 defect showed marked response to both PARP inhibitors and platinum-based chemotherapy. Conclusions: Our study explored the genomic landscape of Chinese patients with mCRPC at different treatment stages using minimally invasive methods and evaluated the clinical implications of the driver genomic alterations on patients’ response to the most widely used therapies for mCRPC. We observed a significantly higher alteration frequency of CDK12 in our cohort compared with the SU2C-PCF cohort.

The basal cell compartment in many epithelial tissues is generally believed to serve as an important pool of stem cells. However, basal cells are heterogenous and the stem cell subpopulation within basal cells is not well elucidated. Here we uncover that the core epithelial-to-mesenchymal transition (EMT) inducer Zeb1 is expressed in a prostate basal cell subpopulation. The Zeb1+ prostate epithelial cells are multipotent prostate basal stem cells (PBSCs) that can self-renew and generate functional prostatic glandular structures at the single-cell level. Genetic ablation studies reveal an indispensable role for Zeb1 in prostate basal cell development. Utilizing unbiased single-cell transcriptomic analysis of over 9000 mouse prostate basal cells, we confirm the existence of the Zeb1+ basal cell subset. Moreover, Zeb1+ epithelial cells can be detected in mouse and human prostate tumors. Identification of the PBSC and its transcriptome profile is crucial to advance our understanding of prostate development and tumorigenesis., Heterogeneous populations of basal cells in the prostate epithelium contain stem cells. Here the authors show that Zeb1 marks a pool of prostate epithelial stem cells that self-renew, generate prostate glandular structures with all 3 epithelial cell types and are required for prostate basal cell development.

The correct diagnosis of small cell carcinoma (SCC) of the prostate is critical because of its aggressive behavior and poor prognosis. The histopathologic diagnosis could be challenging without neuroendocrine markers, which currently has limitations. Insulinoma-associated protein 1 (INSM1), a zinc-finger transcription factor, is considered to play an important role in the development of several neuroendocrine precursor cells. Its diagnosis value has only recently been evaluated. In this study, we analyzed the expression of INSM in three high-throughput RNA sequencing data sets and performed INSM1 immunohistochemistry on a large series of prostatic SCCs and non-neuroendocrine prostate tissues. To validate its possible utility as a diagnostic marker, the performance of chromogranin and synaptophysin was used for comparison. We found INSM1 mRNA is up-regulated in neuroendocrine prostate carcinoma samples from the published data sets. The results were verified by the immunohistochemistry performance. INSM1 was positive in 92.3% of prostatic SCCs, compared with 53.8% positive for chromogranin, and 84.6% positive for synaptophysin. INSM1 was also stained all of the mixed SCC-acinar adenocarcinomas and metastatic SCCs progression from acinar adenocarcinoma. Only 3.4% of benign prostate tissues and 4.0% of prostate adenocarcinomas were INSM1 positive. Our data suggest that INSM1 is a novel sensitive and specific marker for detection of SCC of the prostate. Application of INSM1 in clinical pathologic diagnosis will be valuable.

Renal cell carcinoma (RCC) is the most common malignancy of urogenital system, and patients with RCC may face a poor prognosis. However, limited curable therapeutic options are currently available. The aim of this study is to investigate the role of Cannabinoid receptor 2 (CB2) in RCC progression. Immunohistochemistry was to investigate the expression pattern of CB2 in 418 RCC tissues and explore its prognostic function in RCC patients. Furthermore, the role of used CB2 si-RNA knockdown and inhibited by AM630, a CB2 inverse agonist, on cell proliferation, migration, and cell cycle of RCC cell lines in vitro was also investigated. We observed that CB2 was up-regulated in RCC tissues, and presented as an independent prognostic factor for overall survival of RCC patients and higher CB2 expression tends to have poor clinical outcomes in survival analyses. Moreover, we also observed that CB2, incorporated with pN stage, pathological grade, and recurrence or distant metastasis after surgery, could obviously enhance their prognostic accuracy in a predictive nomogram analysis. In addition, knockdown or inhibition by AM630 for the expression of CB2 in vitro could significantly decreased cell proliferation and migration, and obviously induced cell cycle arrest in G2/M of RCC cells. CB2 expression is functionally related to cellular proliferation, migration, and cell cycle of RCC cells. Our data suggest that CB2 might be a potential therapeutic target for RCC.

Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression. Here, we report that the transcription factor HNF1B is downregulated in the majority of ChRCC and that the magnitude of HNF1B loss is unique to ChRCC. We also observed a strong correlation between reduced HNF1B expression and aneuploidy in ChRCC patients. In murine embryonic fibroblasts or ACHN cells, HNF1B deficiency reduced expression of the spindle checkpoint proteins MAD2L1 and BUB1B, and the cell-cycle checkpoint proteins RB1 and p27. Furthermore, it altered the chromatin accessibility of Mad2l1, Bub1b, and Rb1 genes and triggered aneuploidy development. Analysis of The Cancer Genome Atlas database revealed TP53 mutations in 33% of ChRCC where HNF1B expression was repressed. In clinical specimens, combining HNF1B loss with TP53 mutation produced an association with poor patient prognosis. In cells, combining HNF1B loss and TP53 mutation increased cell proliferation and aneuploidy. Our results show how HNF1B loss leads to abnormal mitotic protein regulation and induction of aneuploidy. We propose that coordinate loss of HNF1B and TP53 may enhance cellular survival and confer an aggressive phenotype in ChRCC. Cancer Res; 77(19); 5313–26. ©2017 AACR.

Although serum prealbumin is a sensitive marker to assess malnutrition, its prognostic impact in patients with metastatic renal cell carcinoma (mRCC) remains elusive.Patients' data were retrospectively retrieved from the medical records of Renji Hospital affiliated to Shanghai Jiao Tong University School of Medicine from March 2006 to July 2015 to access overall survival (OS) and progression-free survival (PFS). The survival outcomes of patients with low pretreatment prealbumin (200 mg/L) and high pretreatment prealbumin (≥ 200 mg/L) were compared using a log-rank test and Cox proportional hazard regression model. Prognostic accuracy was determined using the Harrell concordance index (c-index).The median PFS and OS for 143 patients were 11 months (95% confidence interval [CI], 9-14 months) and 27 months (95% CI, 22-39 months), respectively. The low pretreatment prealbumin group had significantly shorter median PFS (6 vs. 14 months, P .001) and OS (10 vs. 34 months, P .001) than the normal pretreatment prealbumin group. Multivariate analysis showed that pretreatment prealbumin was an independent predictor of OS (hazard ratio [HR] 1.963; 95% CI, 1.140-3.381; P = .015) and also an independent predictor of PFS (HR 2.021; 95% CI, 1.227-3.329; P = .006). Further, addition of pretreatment prealbumin to the Heng model enhanced the predictive accuracy of PFS and OS (c-index: 0.70 and 0.74) compared with the Heng model alone (c-index: 0.69 and 0.72).Low pretreatment serum prealbumin is an independent prognosticator of risk and survival outcomes in patients with mRCC receiving tyrosine kinase inhibitors as first-line treatment and also increases the accuracy of established prognostic models.

Background To determine the influence of abiraterone Acetate (AA) on neuroendocrine differentiation (NED) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). Methods We conducted an analysis in 115 chemotherapy-naive mCRPC patients who would be treated with chemotherapy. The serum levels of chromogranin A (CgA), neurone-specific enolase (NSE) were measured in 67 mCRPC patients without AA treatment and 48 patients after the failure of AA treatment, in which these markers were also measured in 34 patients before and after 6 months of AA treatment. Comparative t-test was used to evaluate the serial changes of serum NED markers during AA treatment and univariate and multivariate analyses were performed to test the influence of AA treatment on NED. Results Serum CgA were NSE were evaluated to be above the upper limit of normal (ULN) in 56 (48.7%) and 29 (25.2%) patients before chemotherapy. In 34 patients with serial evaluation, serum CgA level of 14 patients and NSE of 14 patients increased after the failure of AA treatment. There was no significant difference of NED markers (CgA or NSE variation (P = 0.243) between at baseline and after the failure of AA treatment. Compared with the CgA elevation group in the first 6 months of AA treatment and baseline supranormal CgA group, the CgA decline group, and baseline normal CgA group has a much longer median PSA PFS (14.34 vs 10.00 months, P

Increasing evidence indicates that inflammation may play important roles in tumorigenesis and progression, and an elevated peripheral monocyte count predicts a poor prognosis in various types of malignancies. Here, we evaluate the roles of peripheral monocyte count in the diagnosis and prognosis for prostate cancer in Chinese patients. A total of 1107 consecutive patients who had undergone prostate biopsy and 290 prostate cancer patients receiving androgen deprivation therapy as first-line therapy were retrospectively analyzed. The parameters were measured at the time of diagnosis. Univariate and multivariate logistic regression analyses were performed to identify the independent predictors of a positive biopsy. Patients were categorized in two groups using a cutoff point of 0.425 × 109 l−1 as calculated by the receiver-operating curve analysis for prognosis. Univariate and multivariate Cox regression analyses were performed to determine the associations of monocyte count with progression-free survival, cancer-specific survival, and overall survival. Multivariate logistic regression analyses showed that monocyte count, age, prostate-specific antigen (PSA), free/total PSA, and prostate volume were independent predictors for prostate cancer. Multivariate Cox regression analyses identified an elevated monocyte count as an independent prognostic factor for worse cancer-specific survival (hazard ratio = 2.244, P < 0.05) and overall survival (hazard ratio = 1.995, P < 0.05), but not progression-free survival (P = 0.117). Our results indicated that an elevated monocyte count was an independent diagnostic biomarker for prostate cancer, and pretreatment peripheral monocyte count might play a significant role in the prognosis of prostate cancer patients treated with androgen deprivation therapy.

// Jianjun Sha 1, 2, * , Wei Xue 1, * , Baijun Dong 1 , Jiahua Pan 1 , Xiaorong WU 1 , Dong Li 1 , Dongming Liu 1 , Yiran Huang 1, 2 1 Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China 2 School of Biomedical Engineering, Shanghai Jiaotong University, Shanghai, People’s Republic of China * Co-first authors Correspondence to: Yiran Huang, email: huangyiran_sh@sina.com Keywords: PRKAR2B, castration resistant, prostate cancer, CRPC, cell cycle Received: July 11, 2016 Accepted: December 13, 2016 Published: December 20, 2016 ABSTRACT Castration-resistant prostate cancer (CRPC) is an advanced form of prostate cancer. Despite some progresses have been made, the mechanism of CRPC development is still largely unknown, including the genes involved in its development have not been well defined. Here, we identified PRKAR2B to be a gene over-expressingin castration-resistant prostate cancer by analyzing the different online databases. Followed functional validation experiments showed that PRKAR2B promoted CRPC cell proliferation and invasion, and inhibited CRPC cell apoptosis. Whole genome transcriptome and GO enrichment analyses of the knock-down of PRKAR2B in CRPC cells showed that PRKAR2B mainly accelerated cell cycle biological process and modulated multiple cell cycle genes, such as CCNB1 , MCM2 , PLK1 and AURKB . Our study firstly identified PRKAR2B as a novel oncogenic gene involved in CRPC development and suggested it is a promising target for the future investigation and the treatment of CRPC.

Protein-protein interactions are spatially regulated in living cells to realize high reaction efficiency, as seen in naturally existing electron-transfer chains. Nevertheless, arrangement of chemical/biochemical components at the artificial device interfaces does not possess the same level of control. Here we report a tetrahedral DNA framework-enabled bulk enzyme heterojunction (BEH) strategy to program the multi-enzyme catalytic cascade at the interface of electrochemical biosensors. The construction of interpenetrating network of BEH at the millimeter-scale electrode interface brings enzyme pairs within the critical coupling length (CCL) of ~10 nm, which in turn greatly improve the overall catalytic cascade efficiency by ~10-fold. We demonstrate the BEH generality with a range of enzyme pairs for electrochemically detecting clinically relevant molecular targets. As a proof of concept, a BEH-based sarcosine sensor enables single-step detection of the metabolic biomarker of sarcosine with ultrasensitivity, which hold the potential for precision diagnosis of early-stage prostate cancer., Tetrahedral DNA framework-enabled bulk enzyme heterojunctions have been used to program biosensor interfaces. Here, the authors use DNA tetrahedrons to tether enzymes of an enzymatic cascade to gold electrodes, hence raising them over the bulk solution, which led to improved kinetics and sensitivity.

Purpose To predict Gleason grade group (GG) upgrade in biopsy Gleason grade group 1 (GG1) prostate cancer (CaP) patients using surface-enhanced Raman spectroscopy (SERS). Materials and methods Preoperative serum samples of patients with biopsy GG1 and subsequent radical prostatectomy were analyzed using SERS. The role of clinical variables and distinctive SERS spectra in the prediction of GG upgrade were evaluated. Principal component analysis and linear discriminant analysis (PCA-LDA) were used to manage spectral data and develop diagnostic algorithms. Results A total of 342 preoperative serum SERS spectra from 114 patients were obtained. SERS detected a higher level of circulating free nucleic acid bases and a lower level of lipids in patients with GG upgrade to GG3 and higher, presenting as SERS spectral peaks of 728 cm−1 and 1,655 cm−1, respectively. Both spectral peaks were independent predictors of GG upgrade and their addition to clinical predictors of PSA and positive core percent significantly improved predictive power of the logistic regression model with area under curve improved from 0.65 to 0.80 (P = 0.0045). Meanwhile, PCA-LDA diagnostic model based on serum SERS spectra showed a high accuracy of 91.2% in predicted groups and remained stable with a sensitivity, specificity, and accuracy of 65%, 97.3%, 86.0%, respectively when validated by leave-one-out cross-validation method. Conclusions By analyzing preoperative serum samples, SERS combined with PCA-LDA model could be a promising tool for prediction of Gleason GG upgrade in biopsy GG1 CaP and assist in treatment decision-making in clinical practice.

Background Mechanisms driving the progression of castration-resistant prostate cancer are believed to relate substantially to the tumor microenvironment. However, the cross-talks between tumor epithelial cell, stromal cells, and immune cells are yet to be fully elucidated. The present study aims to determine the role of chemokine and neutrophil derived cytokine paracrine axis in mediating the interaction between tumor cells, stromal myofibroblasts, and neutrophils in the tumor microenvironment of prostate cancer. Methods To identify myofibroblasts and neutrophil derived specific proteins affecting progression of prostate cancer, bioinformatics analyses were firstly performed in independent human prostate cancer gene expression data sets from the GEO data bank. Expression of stromal myofibroblasts secretory chemokine CXCL1 and neutrophil derived cytokine LCN2 was evaluated in prostate tissues via immunohistochemistry assay. We further investigated the effect of CXCL1 and LCN2 on prostate cancer using in vivo and in vitro models, and explored the underlying signal transduction pathways. Results A CXCL1-LCN2 paracrine network was confirmed in prostate cancer tissue samples, which was correlated with the biochemical recurrence of prostate cancer. Of note, CXCL1-LCN2 axis activates Src signaling, triggers the epithelial-mesenchymal transition (EMT), consequently promotes the migration of prostate cancer cells, leading to enhanced tumor metastasis. Conclusions Our findings may provide enhanced insight into the interactions of carcinoma-stromal cells and immune cells linked to prostate cancer progression, wherein CXCL1-LCN2 axis is a key contributor to prostate cancer cells migration. These data indicate tumor microenvironment and Src signaling pathway may be potential therapeutic targets of prostate cancer treatment.

Background Chronic lymphocytic leukemia is a malignancy with good prognosis. However, the incidence of secondary tumors increases every year after the diagnosis of chronic lymphotcytic leukemia. One of the induced secondary tumors is prostate cancer. For high-risk prostate cancer in particular, the standard therapy is radical prostatectomy and extended lymphadenectomy, which carries high risks of lymphatic leakage and reduced quality of life. Currently, there has been no study reporting the necessity of extended lymphadenectomy for high-risk prostate cancer in patients with chronic lymphocytic leukemia. Case presentation We reported two cases with concomitant high-risk prostate cancer and chronic lymphocytic leukemia. The first patient was a 60-year-old male diagnosed with synchronous prostate cancer and chronic lymphocytic leukemia. The second patient was a 70-year-old male initially presented with chronic lymphocytic leukemia alone but was then diagnosed with high-risk prostate cancer nine years later. Both patients received neoadjuvant androgen deprivation therapy and robot-assisted radical prostatectomy. The first patient underwent extended lymphadenectomy and developed prolonged postoperative lymphatic cyst. Histology showed chronic lymphocytic leukemia infiltration in resected lymph nodes. Serum prostate-specific antigen levels at one and 13 months post-operation were both 0.01 ng/ml. The second patient received positron emission tomography/computed tomography before androgen deprivation therapy, which showed mild fluorodeoxyglucose-avidity in lymph nodes across the entire body. Lymph node biopsy showed only chronic lymphocytic leukemia. The patient experienced no postoperative complication. Serum prostate-specific antigen levels at one and nine months post-operation were both 0.02 ng/ml. Conclusions Extended lymphadenectomy may not be necessary for patients with concomitant high-risk prostate cancer and chronic lymphocytic leukemia, but such patients must undergo thorough preoperative assessment and mindful postoperative follow-up. Positron emission tomography/computed tomography may be valuable in detecting nodal metastases. A lymph node biopsy is necessary for patients with an ambiguous positron emission tomography/computed tomography in the metastatic involvement of lymph node.

Castration-resistant prostate cancer (CRPC) causes most of the deaths in patients with prostate cancer (PCa). The androgen receptor (AR) axis plays an important role in castration resistance. Emerging studies showed that the lysine demethylase KDM4B is a key molecule in AR signaling and turnover, and autophagy plays an important role in CRPC. However, little is known about whether KDM4B promotes CRPC progression by regulating autophagy. Here we used an androgen-independent LNCaP (LNCaP-AI) cell line to assay aberrant KDM4B expression using qPCR and western blot analysis and investigated the function of KDM4B in regulating cell proliferation. We found that KDM4B was markedly increased in LNCaP-AI cells compared with LNCaP cells. KDM4B level was significantly correlated with the Gleason score in PCa tissues. In vitro, KDM4B overexpression in CRPC cells promoted cell proliferation, whereas knockdown of KDM4B significantly inhibited cell proliferation. Upregulated KDM4B contributed to activate Wnt/β-catenin signaling and autophagy. Moreover, KDM4B activated autophagy by regulating the Wnt/β-catenin signaling. Finally, we demonstrated that autophagy inhibition attenuated KDM4B-induced CRPC cell proliferation. Our results provided novel insights into the function of KDM4B-driven CRPC development and indicated that KDM4B may be served as a potential target for CRPC therapy.

To evaluate the ability of the new Gleason grade groups (GGGs) to stratify risk in prostate cancer patients with locally adverse pathologic features after radical prostatectomy (RP) thereby allowing more accurate assessment for planning eventual adjuvant therapy.Data on 172 patients with locally adverse pathologic features (including seminal vesicle invasion, extracapsular extension, or positive surgical margins) who had been treated with wait and see policy after RP were retrospectively analyzed for biochemical recurrence (BCR)-free survival. Kaplan-Meier survival analysis and Cox proportional hazard regression models were used to test the association between the GGGs and BCR. Finally, concordance indices of different grading classifications were calculated to evaluate the predictive accuracy for biochemical failure after RP.The five-year BCR-free survival rates were 71.2, 66.9, 25.7, 17.4, and 8.3 % for GGG 1-5 assessed on surgical specimens (p 0.001, log-rank test). In the two-way log-rank test, men with prostatectomy GGG 2 had a lower progression risk relative to GGG 3 (p = 0.001), though similar risk as GGG 1 (p = 0.105). In multivariate Cox regression analysis, specimen GGG ≥3 and early postoperative PSA ≥0.1 ng/ml were independent risk factors for biochemical failure (p 0.001). In addition, GGGs had higher predictive accuracy compared with the alternate classification system (improvement in concordance index by 0.036-0.141).For the appropriate patient, depending on age, physical condition, early postoperative PSA, patient desire, etc., could be a candidate for wait and see policy with specimen GGG 2 disease, so to distinguish this from GGG 3 may facilitate discussions at the point of treatment decision making.

// Fan Xu 1, * , Yujing Gao 2, * , Yanqing Wang 1, * , Jiahua Pan 1, * , Jianjun Sha 1 , Xiaoguang Shao 1 , Xunlei Kang 3 , Jun Qin 1, 4, 5 , M. James You 6, 7 , Yiran Huang 1 , Baijun Dong 1 , Wei Xue 1 1 Department of Urology, RenJi Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China 2 Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, Ningxia Medical University, Yinchuan, Ningxia, China 3 Division of Oncology, Department of Medicine, University of Missouri School of Medicine, Columbia, MO, USA 4 Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China 5 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA 6 Program of Genes and Development, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA 7 Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA * These authors have contributed equally to this work Correspondence to: Baijun Dong, email: dongbaijun@hotmail.com Wei Xue, email: xuewei@renji.com Keywords: prostate cancer, TSPAN1, progression, prognosis, biochemical recurrence Received: April 13, 2016 Accepted: August 10, 2016 Published: August 20, 2016 ABSTRACT Patients with prostate cancer (PCa) have a variable prognosis. It is challenging to recognize the progressive disease. In this study, we focused on TSPAN1, a new member of the tetraspanin family. Its expression was decreased in progressive PCa and was an independent prognosis factor of biochemical recurrence after radical prostatectomy. In vitro , knockdown and overexpression of TSPAN1 in PCa cell lines showed that TSPAN1 could inhibit cell proliferation and migration. TSPAN1 was positive related to PTEN in both clinical specimen and mouse models. The combination of these two markers could increase their prognosis value especially in low risk patients. In vitro TSPAN1 knockdown resulted in increased Akt phosphorylation and caused evident cell cycle transition from G1 to S phase. Our data suggests that TSPAN1 is a valuable marker to recognize more progressive PCa.

Tumor recurrence is still a major challenge for clinical treatment of bladder cancer. Cumulative evidences indicate cancer stem cells (CSCs) contribute to drug resistance and leave a putative source for disease relapse. Identifying novel agents targeting CSCs may represent a new paradigm in the therapy of bladder cancer. Here, we separated a novel hedgehog (Hh) inhibitor, iG2, from streptomyces roseofulvus, which dramatically blocked the activation of Gli2 in bladder cancer cells. The iG2 strongly repressed the growth of cancer cells rather than the peri‐tumor stroma cells. Attenuated proliferation and enhanced apoptosis of tumor cells were observed upon iG2 stimulation. Furthermore, iG2 reduced the self‐renewal ability of bladder CSCs as well as the tumor formation. Collectively, iG2 is potentially used as a novel therapeutic agent for bladder cancer by targeting self‐renewal through inhibiting Hh pathway.

// Hong Zheng 1 , Jiansong Ji 2 , Liangcai Zhao 1 , Minjiang Chen 1, 2 , An Shi 3 , Linlin Pan 1 , Yiran Huang 3 , Huajie Zhang 1 , Baijun Dong 3 , Hongchang Gao 1 1 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China 2 Lishui Central Hospital, The Fifth Affiliated Hospital, Wenzhou Medical University, Lishui, 323000, China 3 Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China Correspondence to: Hongchang Gao, email: gaohc27@wmu.edu.cn Baijun Dong, email: dongbaijun@hotmail.com Keywords: artificial intelligence, early diagnosis, metabolome, metabolic recovery, precision medicine Received: March 22, 2016 Accepted: July 09, 2016 Published: July 24, 2016 ABSTRACT Diagnosis of renal cell carcinoma (RCC) at an early stage is challenging, but it provides the best chance for cure. We aimed to develop a predictive diagnostic method for early-stage RCC based on a biomarker cluster using nuclear magnetic resonance (NMR)-based serum metabolomics and self-organizing maps (SOMs). We trained and validated the SOM model using serum metabolome data from 104 participants, including healthy individuals and early-stage RCC patients. To assess the predictive capability of the model, we analyzed an independent cohort of 22 subjects. We then used our method to evaluate changes in the metabolic patterns of 23 RCC patients before and after nephrectomy. A biomarker cluster of 7 metabolites (alanine, creatine, choline, isoleucine, lactate, leucine, and valine) was identified for the early diagnosis of RCC. The trained SOM model using a biomarker cluster was able to classify 22 test subjects into the appropriate categories. Following nephrectomy, all RCC patients were classified as healthy, which was indicative of metabolic recovery. But using a diagnostic criterion of 0.80, only 3 of the 23 subjects could not be confidently assessed as metabolically recovered after nephrectomy. We successfully followed-up 17 RCC patients for 8 years post-nephrectomy. Eleven of these patients who diagnosed as metabolic recovery remained healthy after 8 years. Our data suggest that a SOM model using a biomarker cluster from serum metabolome can accurately predict early RCC diagnosis and can be used to evaluate postoperative metabolic recovery.

Summary Regulation of prostate epithelial progenitor cells is important in prostate development and prostate diseases. Our previous study demonstrated a function of autocrine cholinergic signaling (ACS) in promoting prostate cancer growth and castration resistance. However, whether or not such ACS also plays a role in prostate development is unknown. Here, we report that ACS promoted the proliferation and inhibited the differentiation of prostate epithelial progenitor cells in organotypic cultures. These results were confirmed by ex vivo lineage tracing assays and in vivo renal capsule recombination assays. Moreover, we found that M3 cholinergic receptor (CHRM3) was upregulated in a large subset of benign prostatic hyperplasia (BPH) tissues compared with normal tissues. Activation of CHRM3 also promoted the proliferation of BPH cells. Together, our findings identify a role of ACS in maintaining prostate epithelial progenitor cells in the proliferating state, and blockade of ACS may have clinical implications for the management of BPH., Highlights • There is autocrine cholinergic signaling (ACS) in developing mouse prostate • ACS regulates proliferation and differentiation of prostate epithelial progenitors • ACS regulates prostate development through calcium signaling • CHRM3 is upregulated in a subset of BPH tissues compared with normal tissues, In this study, Gao, Yang, and colleagues demonstrated the existence of autocrine cholinergic signaling (ACS) in developing mouse prostate. They found that ACS regulates prostate development via affecting proliferation and differentiation of epithelial progenitor cells. Furthermore, CHRM3 expression was upregulated in a subset of clinical benign prostatic hyperplasia (BPH) tissues compared with normal tissues, implicating its possible involvement in BPH.

Renal cell carcinoma (RCC) is frequently diagnosed at advanced stages of disease, although early diagnosis has much favorable prognosis. This study assessed aberrant expression of cytosolic carboxypeptidase 6 (CCP6) leading to accumulation of serum polyglutamylated DNAJC7 as a biomarker for early RCC detection. A total of 835 RCCs, 143 chronic nephritis, 170 kidney stones and 415 health controls were collected for qRT-PCR, immunohistochemistry and Western blot analysis of CCP6 expression and mass spectrometry of DNAJC7 and polyglutamylated DNAJC7. The data showed that CCP6 expression was significantly decreased in 30 RCC tissues and that mass spectrometric and pull-down analysis identified DNAJC7 as a substrate of CCP6 and showed upregulated polyglutamylated-DNAJC7 (polyE-DNAJC7) in sera of RCC patients. The electrochemiluminescence immunoassay of large-scale serum samples from multi-institutes further confirmed the remarkable increase of polyE-DNAJC7 in 805 RCCs compared to that of 385 healthy controls (p < 0.001), 128 patients with chronic nephritis (p < 0.001), and 153 with kidney stone (p < 0.001). Serum level of DNAJC7-polyE protein was also associated with advanced RCC stage and grade in 805 patients. The data from the current study for the first time demonstrated increased serum polyglutamylated DNAJC7 as a potential biomarker for RCC early detection and association with advanced tumor stages and grade, which provides support of further polyglutamylation research in RCC.

Hyperfibrinogen is thought to be associated with a higher risk of invasion and metastasis, as well as a worse outcome for multiple types of cancer. However, the prognostic significance of plasma fibrinogen has not been investigated in prostate cancer with hormonal therapy. The objective of this study was to evaluate its roles in prostate cancer patients treated with androgen deprivation therapy (ADT).A total of 290 patients who underwent ADT as first-line therapy for prostate cancer were retrospectively analyzed. The fibrinogen level was measured at the time of diagnosis. Patients were categorized using a cutoff point of 3.225 g l(-1) according to a calculation by the receiver operating curve analysis. Correlations between the fibrinogen and clinical characteristics were analyzed. Meanwhile, univariable and multivariable cox regression analyses were performed to determine the associations of fibrinogen with progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Prognostic accuracy was evaluated with the Harrell concordance index.Compared with patients with a lower fibrinogen level (3.225 g l(-1)), patients with a higher fibrinogen level were more likely to have higher PSA, Gleason score, risk stratification and incidence of metastasis (P0.05). Multivariable analyses identified hyperfibrinogen as an independent prognostic factor for PFS (hazard ratio (HR)=2.000, P0.001), CSS (HR=2.209, P=0.006) and OS (HR=1.965, P=0.009). The final models built by the addition of fibrinogen improved predictive accuracy (c-index: 0.750, 0.799 and 0.767) for PFS, CSS and OS compared with the clinicopathological base models (c-index: 0.730, 0.778 and 0.746), which included Gleason score and metastasis.The pretreatment plasma fibrinogen level was associated with tumor progression and might have a significant role in the prognosis of the prostate cancer patients treated with ADT. Thus, we recommend adding fibrinogen to traditional prognostic model, which may improve its predictive accuracy.

TIKI2 is a negative regulator of the Wnt family. Although many Wnt antagonists play important roles in renal cell carcinoma (RCC), the molecular function of TIKI2 in human RCC has not been fully elucidated. Here, we analyzed TIKI2 mRNA level in RCC specimens, the corresponding non-tumor tissues, RCC cell lines, and human proximal tubule epithelial cell line HK-2 using qPCR. We demonstrated that TIKI2 was highly expressed in RCC tissue (P < 0.05) and most RCC cell lines. In vitro, TIKI2 knockdown significantly inhibited proliferation, invasion, and clone formation ability of 769-P cells compared with controls, while ectopic TIKI2 expression enhanced A498 cell proliferation, invasion, and clone formation ability. In vivo, the average tumor volume was significantly increased in mice injected with A498-Tiki2 cells (P < 0.05). In the 769-P cell TIKI2 knockdown group, the average tumor volume was not significantly different compared to that of the control group (P = 0.08). Moreover, Wnt/β-catenin signaling was not affected by TIKI2 knockdown or overexpression. Results of the present study indicate that TIKI2 is upregulated in RCC tissues and plays an oncogenic role in RCC.