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Background. A rising amount of data demonstrates that the epithelial-mesenchymal transition (EMT) in clear cell renal cell carcinomas (ccRCC) is connected with the advancement of the cancer. In order to understand the role of EMT in ccRCC, it is critical to integrate molecules involved in EMT into prognosis prediction. The objective of this project was to establish a prognosis prediction model using genes associated with EMT in ccRCC. Methods. We acquired the mRNA expression profiles and clinical information about ccRCC from TCGA database. In this study, we measured differentially expressed EMT-related genes (DEEGs) by two comparison groups (tumor versus normal tissues; “stages I-II” versus “stages III-IV” tumor tissues). Based on classification and regression random forest models, we identified the most important DEEGs in predicting prognosis. Afterwards, a risk-score model was created using the identified important DEEGs. The prediction ability of the risk-score model was calculated by the area under the curve (AUC). A nomogram for prognosis prediction was built using the risk-score in combination with clinical factors. Results. Among the 72 DEEGs, the classification and regression random forest models identified six hub genes (DKK1, DLX4, IL6, KCNN4, RPL22L1, and SPDEF), which exhibited the highest importance values in both models. Through the expression of these six hub genes, a novel risk-score was developed for the prognosis prediction of ccRCC. ROC curves showed the risk-score performed well in both the training (0.749) and testing (0.777) datasets. According to the survival analysis, individuals who were separated into high/low-risk groups had statistically different outcomes in terms of prognosis. Besides, the risk-score model also showed outstanding ability in assessing the progression of ccRCC after treatment. In terms of nomogram, the concordance index (C-index) was 0.79. Additionally, we predicted the differences in response to chemotherapy drugs among patients from low- and high-risk groups. Conclusion. Gene signatures related to EMT could be useful in predicting ccRCC prognosis.

This study sought to provide contemporary data from a multi-institution with respect to DNA-repair genes (DRGs) status and its impact on effects of platinum-based chemotherapy in treatment-emergent neuroendocrine prostate cancer (t-NEPC), for which little data exist.All patients were retrospectively collected with eligible biopsied tissues for targeted next generation sequencing (NGS). The main outcomes were radiologic progression-free survival and overall survival according to Response Evaluation Criteria in Solid Tumors, version 1.1.Among the 43 NEPC patients, 13/43 (30%) harbored homozygous deletions, deleterious mutations, or both in DRGs. Eleven patients (11/13, 85%) with DRGs aberrations had effective response, including 7 patients with BRCA1/2 defects and 2 with mismatch repair-deficient caused by MSH2 alterations. While significantly fewer responders (30%) were detected in patients without DRGs aberrations (odds ratio = 12.83, p = 0.003). Compared with patients without genomic DRGs aberrations, the hazard ratio (HR) for radiologic progression in those with DRGs defects was 0.42 (95% confidence interval [CI]: 0.19-0.93), and the HR for death was 0.65 (95% CI: 0.24-1.72). The most common adverse event of Grade 3 or 4 was anemia, as noted in 7 patients (16%).The DRGs status is therapeutically meaningful in t-NEPC. Given the potential responses to platinum-based chemotherapy, our findings support the clinical use of NGS in t-NEPC patients to identify DRGs aberrations.

Background: The six-transmembrane epithelial antigen of the prostate 3 (STEAP3) plays an essential role in iron uptake as an iron reductase. Previous studies found that STEAP3 may play crucial roles in tumorigenesis. However, a comprehensive pan‐cancer analysis of the prognosis and immunity of STEAP3 has not yet been reported. Methods: We performed a systematic analysis of the prognosis and immunity of STEAP3 in human pan-cancer. The data analysis and visualization were completed with R and Cytoscape. STEAP3 expression in cell lines and tissues was measured in multiple ways. Functional validation experiments were performed by shRNA knockdown inA498 and 786-O cell lines. Cell proliferation and invasive ability was detected by CCK-8 assay, transwell assay and wound healing assay. Results: In most tumor tissues, STEAP3 expression was remarkably upregulated and correlated with prognosis, particularly in clear cell renal cell carcinoma (ccRCC). Furthermore, STEAP3 expression was closely correlated with immune infiltrates and may induce recruitment and polarization of M2 macrophages in ccRCC. STEAP3 may be valuable for predicting responses to immune-checkpoint blockade (ICB) therapy. In addition, enrichment analysis results indicated that STEAP3 was positively related to immune-related pathways, P53 pathways and epithelial-mesenchymal transition (EMT). Finally, we demonstrated that STEAP3 was highly expressed in ccRCC tissues and might stimulate EMT via the downregulation of CDH1 in vitro in ccRCC. Conclusion: STEAP3 might function as a prognostic biomarker and immunotherapy response predictor in various cancers. Especially in ccRCC, STEAP3 is a new prognostic biomarker and exerts tumor-promoting function via stimulating the invasion and EMT and inducing recruitment and polarization of M2 macrophages.

Castration-resistant prostate cancer (CRPC) is a highly malignant type of advanced cancer resistant to androgen deprivation therapy. One of the important mechanisms for the development of CRPC is the persistent imbalanced regulation of AR and AR splice variants (AR/AR-Vs). In this study, we reported KDM4A-AS1, a recently discovered lncRNA, as a tumor promoter that was significantly increased in CRPC cell lines and cancer tissues. Depletion of KDM4A-AS1 significantly reduced cell viability, proliferation, migration in vitro, and tumor growth in vivo. We found that by binding to the NTD domain, KDM4A-AS1 enhances the stability of USP14-AR/AR-Vs complex, and promoted AR/AR-Vs deubiquitination to protect it from MDM2-mediated ubiquitin-proteasome degradation. Moreover, KDM4A-AS1 was found to enhance CRPC drug resistance to enzalutamide by repressing AR/AR-Vs degradation; antisense oligonucleotide drugs targeting KDM4A-AS1 significantly reduced the growth of tumors with enzalutamide resistance. Taken together, our results indicated that KDM4A-AS1 played an important role in the progression of CRPC and enzalutamide resistance by regulating AR/AR-Vs deubiquitination; targeting KDM4A-AS1 has broad clinical application potential.

Aims: We aimed to determine whether intronic circRNA acts as a molecular sponge in castration-resistant prostate cancer (CRPC). Materials & methods: A gene chip technique was used to conduct sequencing. A qPCR experiment was performed to verify the result. Radioimmunoprecipitation, RNA pull-down and dual-luciferase reporter assays were performed to particularly expound its function. Verification of downstream effects was carried out through qPCR and western blot, and a xenograft assay was performed in vivo for verification. Results: Intronic circRNA hsa_circ_0092339 in the nucleus was highly expressed in CRPC cell lines. hsa_circ_0092339 did not regulate the expression of its parental gene. hsa_circ_0092339 functions like a molecular sponge, preventing degradation of C-MYC mRNA by absorbing hsa-mir-940. Conclusion: hsa_circ_0092339 plays a critical role in CRPC through targeting C-MYC indirectly by absorbing hsa-mir-940.

Alzheimer’s disease (AD) is a neurodegenerative disease hallmarked by impaired cognitive function and memory decline; it is accompanied by a variety of mental symptoms and behavioral disorders. This disease has a serious impact on society, families, and the afflicted patients. Curcumin (Cur) nanoparticles were preparation by modifying curcumin with polyethylene glycol-polylactic acid (PEG-PLA) amphiphilic block copolymer. The resulting nanodrug can successfully penetrate the blood brain barrier (BBB) and concentrate in the main pathological areas of AD. As measured with a Zeta particle size analyzer, the particle size of PEG-PLA/Cur was 100 ± 0.53 nm, and it was electrically neutral. In vitro experiments revealed that PEG-PLA/Cur successfully penetrated the membrane of PC12 cells and inhibited proliferation. PEG-PLA/Cur also exhibited an inhibitory effect on the production of amyloid β protein (Aβ fiber) and depolymerization activity on Aβ fiber aggregates. PEG-PLA/Cur represents a novel nanodrug with the potential to treat AD.

In recent years, genes associated with N6-methyladenosine (m6A) modification were found to participate in modulation of multiple tumor biological processes. Concomitantly, the significantly complicated dual effects of tumor microenvironment have been observed on cancer progression. The present study aims to investigate m6A-related immune genes (m6AIGs) for their signatures and prognostic values in bladder cancer (BC). Out of 2856 differentially expressed genes (DEGs) of BC, a total of 85 genes were obtained following intersection of DEGs, immune genes and m6A-related genes. The results of multivariate Cox regression analysis illustrated four genes (BGN, GRK5, IL32, and SREBF1) were significantly associated with the prognosis of BC patients. The BC samples were divided into two types based on the consensus clustering, and the principal component analysis demonstrated a separation between them. It was found that high expression of BGN and GRK5 were linked with advanced T and N stage, and the expression of SREBF1 in early T stage was higher than that in advanced T stage. Subsequently, the nomogram to predict 3- and 5-year survival probability of BC patients was developed and calibrated. GSEA analysis for risk subgroups showed WNT and TGF-beta signaling pathways were involved in regulation of BC progression in high risk level group. In the low risk level group, cytosolic DNA-Sensing cGAS-STING and RIG-I-like receptors signaling pathways were found to be correlated with BC development. These findings provide a novel insight on studies for BC progression., Graphical abstract

Background Cancer-associated fibroblasts (CAFs) are an important part of the tumour microenvironment, and their functions are of great concern. This series of experiments aimed to explore how Yes-associated protein 1 (YAP1) regulates the function of stromal cells and how the normal fibroblasts (NFs) convert into CAFs in prostate cancer (PCa). Methods The effects of conditioned media from different fibroblasts on the proliferation and invasion of epithelial cells TrampC1 were examined. We then analysed the interaction between the YAP1/TEAD1 protein complex and SRC, as well as the regulatory function of the downstream cytoskeletal proteins and actins. A transplanted tumour model was used to explore the function of YAP1 in regulating tumour growth through stromal cells. The relationship between the expression of YAP1 in tumour stromal cells and the clinical characteristics of PCa patients was analysed. Results The expression level of YAP1 was significantly upregulated in PCa stromal cells. After the expression level of YAP1 was increased, NF was transformed into CAF, enhancing the proliferation and invasion ability of epithelial cells. The YAP1/TEAD1 protein complex had the capability to influence downstream cytoskeletal proteins by regulating SRC transcription; therefore, it converts NF to CAF, and CAF can significantly promote tumour growth and metastasis. The high expression of YAP1 in the tumour stromal cells suggested a poor tumour stage and prognosis in PCa patients. Conclusion YAP1 can convert NFs into CAFs in the tumour microenvironment of PCa, thus promoting the development and metastasis of PCa. Silencing YAP1 in tumour stromal cells can effectively inhibit tumour growth.

In PTEN-deficient prostate cancers, AKT signaling may be activated upon suppression of androgen receptor signaling. Activation of AKT as well as NF-κB signaling involves a key regulatory protein complex containing PHLPP, FKBP51 and IKKα. Here, we report a critical role of lncRNA PCAT1 in regulating the PHLPP/FKBP51/IKKα complex and progression of castration-resistant prostate cancer (CRPC). Using database queries, bioinformatic analyses, as well as RIP and RNA pull-down assays, we discovered and validated that the lncRNA-PCAT1 perturbs the PHLPP/FKBP51/IKKα complex and activates AKT and NF-κB signaling. Expression of lncRNA-PCAT1 is positively linked to CRPC progression. PCAT1 binds directly to FKBP51, displacing PHLPP from the PHLPP/FKBP51/IKKα complex, leading to activation of AKT and NF-κB signaling. Targeting PCAT1 restores PHLPP binding to FKBP1 leading to suppression of AKT signaling. Preclinical study in a mouse model of CRPC suggests therapeutic potential by targeting lncRNA PCAT1 to suppress CRPC progression. Together, the newly identified PCAT1/FKBP51/IKKα complex provides mechanistic insight in the interplay between AKT, NF-κB and AR signaling in CRPC, and the preclinical studies suggest that a novel role for PCAT1 as a therapeutic target.

Additional file 6.

Additional file 2: Figure S2. YAP1 promotes the proliferation of CAFs A. Western blot was used to detect the protein expression levels of YAP1 and α-SMA after siSRC transfection of CAFs. GAPDH was used as an endogenous reference gene. B. CAFs were treated with vehicle or 10 μM VP for 24 h. The cytoplasmic and nuclear proteins were extracted and measured by western blot. C-D. The MTT assay detected the proliferation of CAFs after YAP1 expression was inhibited by siRNA or VP (10 μM). The absorbance value at a wavelength of 570 nm was detected (*P

Additional file 4.

Additional file 1 Figure S1. YAP1, α-SMA and FAP are upregulated in CAFs A. The mRNA expression levels of YAP1 and α-SMA in CAFs and NFs were detected by qRT-PCR. B. The protein expression levels of YAP1 and α-SMA in CAFs and NFs were detected by western blot. GAPDH was used as an endogenous reference gene. C. Immunofluorescence staining showed the expression level and location of α-SMA and YAP1 in NFs and CAFs. Nuclei were stained with DAPI. The representative images were magnified 400 x.

Additional file 5.

Additional file 3: Figure S3. SRC regulates the invasive ability of epithelial cells through CAFs A. Kaplan-Meier survival analysis of overall survival for SRC expression in PCa. B. Transwell invasion assay for the effect of conditioned medium on the invasive ability of epithelial cells TrampC1 when SRC was inhibited in the CAFs by dasatinib (10 μM) or siRNA. C. Statistical results of the above invasive ability. Five visual field counts were taken for each group, and the ordinate indicates the number of cells invading. (***P

BACKGROUND Kid (kinesin-like DNA binding protein), a member of microtubule-dependent molecular motor proteins, also known as KIF22, is reported to be associated with carcinogenesis and cancer progression in different types of malignant tumor, but the biologic behavior and clinical outcome of KIF22 in prostate cancer (PCa) has not been well studied. This study aimed to analyze the association between KIF22 and clinical outcome in PCa patients. MATERIAL AND METHODS The expression of KIF22 in tumor specimens compared with paired paracancerous tissue from 114 patients undergoing radical prostatectomy was detected by immunohistochemistry; results were verified using The Cancer Genome Atlas (TCGA) database. Subsequently, the relationship between KIF22 expression and clinical prognosis of PCa patients was then statistically analyzed. RESULTS Both immunohistochemistry and database analysis showed that KIF22 was obviously overexpressed in PCa tissues compared with paracancerous tissue. The overexpression of KIF22 at the protein level was significantly related to higher clinical stage (P=0.025), Gleason score (P=0.002), seminal vesicle invasion (P=0.007), and lymph node metastasis (P=0.009). Furthermore, with the overexpression of KIF22 mRNA level in PCa patients, the oncological prognosis of PCa patients was much poorer. CONCLUSIONS High-level expression of KIF22 was related to both tumor progression and adverse clinical outcome. For this reason, KIF22 may become a potential prognostic factor for PCa.

Background: Metastatic castration-resistant prostate cancer (mCRPC) is one of the main contributors to the death of prostate cancer patients. To date, the detailed molecular mechanisms underlying mCRPC are unclear. Given the crucial role of epithelial–mesenchymal transition (EMT) in cancer metastasis, we aimed to analyse the expression and function of Transforming growth factor-beta (TGF-β) signal-associated protein named Sox5 in mCRPC. Methods: The protein expression levels were analysed by western blot, immunohistochemistry and immunofluorescence. Luciferase reporter assays and chromatin immunoprecipitation were employed to validate the target of Sox5. The effect of Smad3/Sox5/Twist1 on PCa progression was investigated in vitro and in vivo. Results: Here, we found that TGF-β-induced EMT was accompanied by increased Sox5 expression. Interestingly, knockdown of Sox5 expression attenuated EMT induced by TGF-β signalling. Furthermore, we demonstrated that Smad3 could bind to the promoter of Sox5 and regulate its expression. Mechanistically, Sox5 could bind to Twist1 promoter and active Twist1, which initiated EMT. Importantly, knockdown of Sox5 in prostate cancer cells resulted in less of the mesenchymal phenotype and cell migration ability. Furthermore, targeting Sox5 could inhibit prostate cancer progression in a xenograft mouse model. In clinic, patients with high Sox5 expression were more likely to suffer from metastases, and high Sox5 expression also has a lower progression-free survival and cancer specific-survival in clinic database. Conclusions: Therefore, we propose a new mechanism in which Smad3/Sox5/Twist1 promotes EMT and contributes to PCa progression.

e17515 Background: Philadelphia Prostate Cancer Consensus Conference 2017 developed an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA. However, the consensus was mainly based on data from Caucasian populations. Genetic differences in the PC molecular landscape between Asian and Caucasian men have been established. Whether Caucasian-based genetic information can be used to guide clinical practice in Chinese population needs further evidence. Methods: 1123 patients with confirmed prostate cancer admitted from March 2018 to August 2019 from 18 Chinese centers were included in this retrospective study. We sequenced the association of 50 gene with prostate cancer risk, clinical treatment implications and predisposition, focusing on DNA repair gene and genetic susceptibility genes pathogenic mutations in Philadelphia Prostate Cancer Consensus Conference. Only protein-truncating alterations (nonsense/stop-gains, frameshift insertions and deletions, and donor and acceptor splice-site mutations) were coded as pathogenic or likely pathogenic protein-truncating alterations. Results: Among all cases, DNA repair gene pathogenic mutations were found in 133 men (11.84%), including BRCA2 (62 [5.5%]), ATM (15 [1.3%]), PALB2 (11 [0.97%]), GEN1 (7 [0.62%]), BRCA1 (6 [0.53%]), MLH3 (4 [0.35%]), MUTYH (4 [0.35%]), PMS1 (4 [0.35%]), RAD50 (4 [0.35%]), ATR (3 [0.27%]), CHEK2 (3 [0.27%]), FANCD2 (3 [0.27%]) etc. Similar germline DRG mutation frequencies were observed between our cohort and Caucasian men. Noticeably, G84E mutation in HOXB13, a rare but recurrent missense mutation associated with a significantly increased risk of hereditary prostate cancer was not found in our cohort of patients. Furthermore, the frequency of HSD3B1 (1245C) allele in the Chinese patients is much lower than that in the Caucasian populations (11.7% vs 63%). Conclusions: Our study retrospectively analyzed germline mutation profile of prostate cancer in Chinese population. The frequency of HSD3B1 (1245C) allele varies across ethnic populations in spite of the similar DNA repair gene mutations rates. Considering the gene list should be tested based on clinical/familial scenarios from the Philadelphia Prostate Cancer Consensus Conference, a prevalence of certain mutations, G84E mutation in HOXB13 was unnecessary for genetic testing in Chinese population.

Castration-resistant prostate cancer (CRPC) with neuroendocrine differentiation (NED) is a lethal disease for which effective therapies are urgently needed. The mechanism underlying development of CRPC with NED, however, remains largely uncharacterized. In this study, we explored and characterized the functional role of neurotensin (NTS) in cell line and animal models of CRPC with NED. NTS was acutely induced by androgen deprivation in animal models of prostate cancer (PCa) and activated downstream signaling leading to NED through activation of neurotensin receptor 1 (NTSR1) and neurotensin receptor 3 (NTSR3), but not neurotensin receptor 2 (NTSR2). Our findings also revealed the existence of a CK8+/CK14+ subpopulation in the LNCaP cell line that expresses high levels of both NTSR1 and NTSR3, and displays an enhanced susceptibility to develop neuroendocrine-like phenotypes upon treatment with NTS. More importantly, NTSR1 pathway inhibition prevented the development of NED and castration resistance in vivo. We propose a novel role of NTS in the development of CRPC with NED, and a possible strategy to prevent the onset of NED by targeting the NTS signaling pathway.

Catalase is an important endogenous antioxidant enzyme that detoxifies hydrogen peroxide to oxygen and water, thus limiting the deleterious effects of reactive oxygen species. Several studies investigated the role of the Catalase (CAT) C-262T gene polymorphism on the risk of prostate cancer (PCa), but get conflicting results. We performed a meta-analysis based on five studies, to determine whether Catalase C-262T polymorphism contributes to the risk of prostate cancer using odds ratios (OR) with 95% confidence intervals (CI). On the whole, our evidence indicates that CAT C-262T polymorphism significantly increases PCa risk in the allele comparison model (OR=1.094, 95% CI=1.015-1.178, P=0.018). In the stratified analysis by ethnicity, the same results are found among Caucasians (allele model, OR=1.090, 95% CI=1.009-1.177, P=0.028, dominant model, OR=1.108, 95% CI=1.023-1.201, P=0.012, recessive model, OR=1.379, 95% CI=1.158-1.641, P=0.000, homozygous model, OR=1.429, 95% CI=1.196-1.707, P=0.000, and heterozygote model, OR=1.224, 95% CI=1.020-1.469, P=0.030). In conclusion, this meta-analysis suggests a positive correlation between Catalase C-262T polymorphism and the development of PCa.

Background The independent prognostic role of squamous differentiation in pT1 bladder urothelial carcinoma has not been reported in previous studies. This article describes the impact of squamous differentiation on tumor recurrence and survival, and whether this histologic variant could indeed alter definitive treatment, based on single center-based retrospective data. Methods Totally, we retrieved (1)1449 histologically confirmed pT1 bladder urothelial carcinoma patients without histologic variants; (2)227 pT1 bladder urothelial carcinoma patients with squamous differentiation in our institution, from May 2004 to Oct 2015. The total amount of high/low grade urothelial carcinoma patients was 991/685 respectively. Transurethral resection of bladder tumor (TURBT) and intravesical chemotherapy were performed as initial treatments for all the patients. The clinical and pathological characteristics, treatment and survival outcomes were compared between squamous differentiation-positive and squamous differentiation-negative patients. Results In our study, 14% urothelial carcinoma patients were detected with squamous differentiation. The mean age of all the patients examined was 66.4, of whom 82% were males. The 5-year cancer specific survival rates were 69% for squamous differentiation-positive patients and 91% for squamous differentiation-negative patients (p

The aim of this study is to explore the oncological outcomes of hypofractionated radiotherapy for patients with prostate cancer. We systematically searched PubMed, Embase, and the Cochrane Library prior to April 2014 and references of relevant original papers and review articles. Unpublished data from meeting abstracts were supplemented. Studies comparing hypofractionated with conventionally fractionated radiotherapy (CFRT) on oncological outcomes of patients with clinically localized prostate cancer were included. Twelve distinct datasets involving 4,572 participants from 13 papers were eligible for this meta-analysis. The biochemical failure rate (BFR) decreases significantly in the hypofractionated radiotherapy (HFRT) group for approximately 30 % (11-43 %). However, no significantly lower prostate cancer-specific survival and overall survival in HFRT group were observed. In subgroup analyses, HFRT without radiation doses reduction was especially effective in controlling BFR (HR = 0.71, 95 % CI 0.53-0.95; P = 0.02). Compared to CFRT, HFRT only yield a consistent advantage on BFR in high-risk patients (HR = 0.61, 95 % CI 0.46-0.82; P = 0.001). Moreover, androgen deprivation therapy (ADT) had no effect on two radiotherapies in controlling BFR. HFRT improves biochemical failure-free survival in patients with clinically localized prostate cancer. Further well-designed trial is needed to confirm our findings.

Background: As deregulation of androgen receptor (AR) signaling target genes is associated with tumorigenesis and the development of prostate cancer (PCa), AR signaling is the primary therapeutic target for PCa. Although patients initially responses to first-line androgen deprivation therapies (ADTs), most of them with advanced PCa progress to lethal castration-resistant prostate cancer (CRPC). Recent studies have suggested the molecular mechanisms by which AR elicit the robust up-regulation of the FKBP51 gene. We suggest that restored expression of FKBP51 gene, modulated by androgen receptor splicing variant 7 (AR- V7) which replaces full length androgen receptor (AR-FL) in androgen ablation status, promotes CRPC progression through activating NF-κB signaling. Methods: Immunohistochemistry assays were used to detect the expression of AR-V7, FKBP51 and NF-κB signaling correlated proteins in CRPC tissues. An androgen ablation resistant PCa cell line model established by Long-term culturing in androgen depleted medium, named androgen-independent LNCaP (LNCaP-AI) cells, were used to dynamically monitor FKBP51 expression during the process of androgen dependent PCa cells transforming into androgen-independent cells, as well as its association with NF-κB signal pathway. LNCaP-AI cell line was determined to express AR-V7 protein continuously. Luciferase reporter assays and DNA pull down were used to determine the association between AR-V7 and FKBP51. Results: Our results suggested that CRPC patients with AR-V7 high expression tend to have higher expression of FKBP51 and enhanced NF-κB signaling compared with AR-V7 negative patients. Knockdown of AR-V7 or FKBP51 in LNCaP-AI cells attenuated the level of p-NF-κB (Ser536) and androgen- resistant cells growth. Luciferase reporter assays and DNA pull down results indicated that FKBP51 was transcriptionally promoted by AR-V7 in absence of androgen, which enhanced NF-κB signaling. Conclusions: Because of upregulation of AR-V7 in androgen-independent PCa cells, increasing of FKBP51 induced NF-κB signaling, leading to progression of CRPC.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

A HOXB13-to-IL17BR expression ratio was previously identified to predict a clinical outcome of breast cancer patients treated with adjuvant tamoxifen. A large number of studies were addressed to confirm its function as a predictor of breast cancer outcome treated with tamoxifen. However, conflicting results were got. In this study, a systematic search of databases was carried out, and other relevant papers were also identified. Then, the analyses were conducted according to the PRISMA and MOOSE guidelines. After full review, 11 studies with a total of 2,958 participants were deemed eligible and were included in the study. Pooled results revealed that women with higher HOXB13-to-IL17BR expression ratio had significantly worse outcomes in breast patients treated with tamoxifen, especially for those who are negative of node.

BACKGROUND. Cell-in-cell phenomenon has been found for more than a century. Entosis, which is a newly found homogeneous cell-in-cell phenomenon and a non-apoptosis cell death progress, has unclear function in prostate cancer progression. Here, we dissected mechanism of AR signaling related to entosis incidence in PCa progression. METHODS. Two stable PCa cell lines, named LNCaP-ARsi and C4-2-ARsi were established with stably transfected AR-shRNA to knockdown AR mRNA expression in LNCaP and C4-2 cells, respectively. PC3-AR9 cell line was also established after stably transfecting full-length AR-cDNA into PC3 cells. All these cells were cultured in poly-HEME-coated plates to induce entosis, which is demonstrated via double staining. RESULTS. Androgen-DHTcould enhance entosis in LNCaP, C4-2 and PC3-AR9 PCa cells in a dose dependent manner. Knock-down of AR in LNCaP and C4-2 significantly suppressed entosis as compared to LNCaP-ARsc and C4-2-ARsc cells at both 1 and 10 nM DHTcondition (P < 0.05). And suppression of Rho/ROCK expression resulted in interruption of ARmediated entosis. Human PCa samples surveys demonstrated that entosis was found only in CRPC but not in BPH and ADPC where AR was less expressed as compared to CRPC. CONCLUSIONS. These results indicated that AR might play a negative role during PCa progression via influencing entosis by modulating Rho/ROCK pathway. This newly identified AR role of enhancing entosis might help us to better understand the multiple and opposite roles of AR, which could either promote or suppress PCa cell progression via different mechanisms. Prostate 73:1306–1315, 2013. # 2013 Wiley Periodicals, Inc.

Context The optimal initial prostate biopsy core number is still an issue with many unanswered questions and significant controversy. Objective To compare diagnostic values of initial saturation prostate biopsy scheme and extended scheme with respect to prostate-specific antigen (PSA) levels, prostate volume (PV), and PSA density (PSAD). Evidence acquisition Electronic databases including Medline, Web of Knowledge, and the Cochrane Library were searched through November 1, 2012. Experts were consulted, and references from relevant articles were scanned. The meta-analysis was conducted with RevMan 5.1, according to the PRISMA guidelines. Mantel-Haenszel estimates were calculated and pooled under a fixed or random effect model, with data expressed as risk difference (RD) and 95% confidence interval (CI). Evidence synthesis We analyzed eight trials with a total of 11997 participants who underwent transrectal ultrasound guided prostate biopsies for the first time and met inclusion criteria. Studies consisted of one paired design study, two randomized clinical trials, and five nonrandomized studies. Saturation biopsy scheme showed a significant advantage in prostate cancer (PCa) detection over an extended scheme (RD: 0.04; 95% CI, 0.01–0.08; p =0.02). In addition, subgroup analyses found a saturation protocol to be superior to an extended protocol in the detection of PCa in men with PSA p =0.002), PV >40ml (RD: 0.05; 95%CI, 0.01–0.09; p =0.02), or PSAD p =0.04). Conclusions The existing evidence indicates that an initial saturation biopsy scheme is more efficient than an extended scheme for PCa detection, especially for those men with lower PSA levels, higher PV, or lower PSAD, without increasing complications and the amount of insignificant cancer.

Homeobox (Hox) genes encode homeodomain-containing transcription factors critical to development, differentiation, and homeostasis. Their dysregulation has been implicated in various cancers. In the present study, we show that HoxB3 mRNA and protein are overexpressed in primary prostate cancer tissues compared to the adjacent normal prostate tissues. Moreover, HoxB3 overexpression is associated with higher Gleason grade (⩾7) (P=0.002), clinical stage (P

Inguinal hernia is widely recognized as a complication after radical prostatectomy. We systematically investigated the risk factors for inguinal hernia, compared the incidence after various surgical procedures and explored prophylactic surgical maneuvers.A systematic search of the literature was performed using Medline®, Web of Knowledge® and the Cochrane Library databases. All analyses and tests were conducted using STATA® software.A total of 31 trials from 29 eligible studies were identified according to the predefined selection criteria. As integrated, postoperative inguinal hernia developed in 15.9% (13.1-18.7) of patients who underwent radical retropubic prostatectomy and 6.7% (4.8-8.6) of those who underwent laparoscopic radical prostatectomy. Most cases of inguinal hernia occurred within the first 2 years after surgery. Right side and indirect-type dominance was found in those inguinal hernias. Pooled results of comparative studies revealed that the incidence of inguinal hernia after radical retropubic prostatectomy was significantly higher than that after no operation, laparoscopic surgery, radical perineal prostatectomy, mini-laparotomy radical retropubic prostatectomy and pelvic lymph node dissection, but was not significantly higher than that after open prostatectomy and cystectomy. In addition, increasing age, low body mass index, subclinical inguinal hernia, previous inguinal hernia repair and anastomotic stricture can increase the risk for inguinal hernia after radical prostatectomy.While some limitations cannot be overcome, this meta-analysis suggests that damage to the posterior layer of the rectus sheath may be involved in the development of inguinal hernia after radical prostatectomy. Prophylactic surgery for high risk subjects is advised at the time of radical prostatectomy to minimize the incidence of inguinal hernia.

Background Whether androgen deprivation therapy (ADT) leads to stroke morbidity is still unclear because of inconsistent evidence. We performed a systematic review and meta-analysis to evaluate if ADT used in men with prostate cancer (PCa) is associated with stroke. Methods and results Medline, Embase and Cochrane Library databases up to September 30th 2014 were systematically searched with no date or language restriction, and reports from potentially relevant journals were complementally searched. Both randomized controlled trials and observational studies were included. Two reviewers independently extracted data and assessed study quality. Six observational studies finally met inclusion criteria, with 74,538 ADT users and 85,947 non-ADT users reporting stroke as an endpoint. Although no significant association was observed in pooled estimates, the incidence of stroke in ADT users was 12 % higher than control groups, (HR = 1.12, 95 % confidence interval [CI]: 0.95 to 1.32; P = 0.16). In subgroup-analyses of different ADT types, stroke was found to be significantly associated with gonadotropin-releasing hormone (GnRH) alone (HR = 1.20, 95 % CI: 1.12 to 1.28; P

Methods S1. Literature Search Strategy. Table S1. List of Excluded Full-text Articles with Reasons for Exclusions. Table S2. Newcastle-Ottawa Scale Quality Assessment of Included Studies. Figure S1. Details of Subgroup Analyses for Stroke Related to Different Types of ADT. Figure S2. Funnel plots for Meta-analyses. (DOC 180 kb)

OBJECTIVE Insulin resistance plays a part in diabetic nephropathy (DN). The association between the peroxisome proliferator–activated receptor γ Pro to Ala alteration at codon 12 (Pro12Ala) polymorphism and the risk of insulin resistance has been confirmed. The association between the polymorphism and DN risk has also been widely studied recently, but no consensus was available up to now. RESEARCH DESIGN AND METHODS A systematic search of electronic databases (MEDLINE, Embase, and China National Knowledge Infrastructure) and reference lists of relevant articles was carried out, and then 18 case-control studies involving 3,361 DN cases and 5,825 control subjects were identified. RESULTS In the overall analysis, the Ala12 variant was observed to be significantly associated with decreased DN risk (odds ratio 0.76 [95% CI 0.61–0.93]). Some evidence of heterogeneity among the included studies was detected, which could be explained by the difference of ethnicity and stage of DN. Subgroup analyses stratified by ethnicity and stage of DN were performed, and results indicated the Pro12Ala polymorphism was associated with the risk of DN in Caucasians but no similar association was observed in Asians. Additionally, we observed that Ala12 was associated with decreased risk of albuminuria. With only a few of subjects were available, we failed to detect statistically significant association between the polymorphism and end-stage renal disease (ESRD). CONCLUSIONS Our results indicated that the Ala12 variant is a significantly protective factor for DN. Future research should focus on the effect of Pro12Ala polymorphism on ESRD and gathering data of Africans.

The association between polymorphism of DNA methyltransferases 3B and cancer risk has been widely studied recently, and no consensus conclusion is available up to now. We perform a comprehensive search using the databases of Medline, ISI Web of Knowledge and Embase. The odds ratio (OR) and its 95% confidence interval (95% CI) are used to investigate the strength of the association. A total of 24 case–control studies with 15,647 individuals are included in this meta-analysis. For −149C > T (17 studies, 5229 cases and 6910 controls), no evidence indicate that individuals carrying the variant genotypes (CC + CT), relative to those carrying the wild homozygote TT genotype, have an increased risk of cancer (OR = 1.03; 95% CI = 0.84–1.26; P = 0.76). Similarly, no cancer risk is found in the subgroup analyses. For −579G > T (11 studies, 3513 cases and 3714 controls), significantly decreased risks of cancer are observed, and the ORs (95% CI) are 0.70 (0.56–0.87) for GT versus TT, 0.70 (0.57–0.85) for GG + GT versus TT and 0.76 (0.63–0.93) for G-allele versus T-allele, respectively. Subgroup analyses stratified by ethnicity and types of cancer are also performed, and results indicated that −579G > C polymorphism is associated with risk of cancer in Asians [0.68 (0.53–0.87) for GT vs. TT] but not in Europeans [0.82 (0.63–1.07) for GT vs. TT]. We also observe that the −579G is associated with decreased risk of colorectal cancer [0.49(0.38–0.62) for GT vs. TT]. More studies with larger sample size were needed to provide more precise evidence.

// Zhiqun Shang 1 , Qiliang Cai 1 , Minghao Zhang 1 , Shimiao Zhu 1 , Yuan Ma 1 , Libin Sun 1 , Ning Jiang 1 , Jing Tian 1 , Xiaodan Niu 2 , Jiatong Chen 3 , Yinghao Sun 4 and Yuanjie Niu 1 1 Sex Hormone Research Center, Tianjin Institute of Urology, the Second Hospital of Tianjin Medical University, Tianjin, China 2 University of Rochester, Rochester, New York, USA 3 Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai university, Tianjin, China 4 Department of Urology, Changhai Hospital of the Second Military Medical University, Shanghai, China Correspondence: Yuanjie Niu, email: // Keywords : androgen deprivation therapy, epithelial-mesenchymal transition, TGFβ1, cancer stem cell, CD44, prostate cancer Received : August 23, 2014 Accepted : November 24, 2014 Published : November 25, 2014 Abstract Epithelial–mesenchymal transition (EMT) has been linked to cancer stem-like (CD44+) cell in the prostate cancer (PCa) metastasis. However, the molecular mechanism remains elusive. Here, we found EMT contributed to metastasis in PCa patients failed in androgen deprivation therapy (ADT). Castration TRAMP model also proved PCa treated with ADT promoted EMT with increased CD44+ stem-like cells. Switched CD44+ cell to EMT cell is a key step for luminal PCa cell metastasis. Our results also suggested ADT might go through promoting TGFβ1-CD44 signaling to enhance swift to EMT. Targeting CD44 with salinomycin and siRNA could inhibit cell transition and decrease PCa invasion. Together, cancer stem-like (CD44+) cells could be the initiator cells of EMT modulated by TGFβ1-CD44 signaling. Combined therapy of ADT with anti-CD44 may become a new potential therapeutic approach to battle later stage PCa.

Background Alpha-methylacyl-CoA racemase (AMACR) is a mitochondrial and peroxisomal enzyme that is overexpressed in prostate cancer. The aim of this study was to confirm and expand the findings that the PCa risk increased in men associated with AMACR expression across various geographic regions. Methods A systematic search of databases was carried out and other relevant articles were also identified. Then the meta-analyses were conducted according to the standard guidelines. Results A total of 22 studies with 4,385 participants were included on the basis of inclusion criteria. AMACR by IHC was significantly associated with increased diagnosis of PCa (OR = 76.08; 95% CI, 25.53–226.68; P