Zhiqun Shang

Germline Homeobox B13 (HOXB13) G84E Mutation and Prostate Cancer Risk in European Descendants: A Meta-analysis of 24 213 Cases and 73 631 Controls

Next-generation sequencing technologies may provide new opportunities to discover disease-related variants through interrogating large genomic intervals in a rapid and comprehensive manner. Through scanning >200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with familial prostate cancer (PCa), Ewing et al. [1] identified a rare but recurrent mutation (G84E) in homeobox B13 (HOXB13) (rs138213197), a homeobox transcription factor gene that is important in prostate development. In an attempt to confirm and expand the findings by Ewing et al., we completed a meta-analysis of HOXB13 G84E mutation in men of European lineage across different geographic regions who had PCa. We undertook a systematic literature review with search terms (see Supplementary Table 1) and hand-searched online journals without language restriction. We restricted the search to Medline, Embase, Web of Science, and the Cochrane Library. The last quest was updated on January 3, 2013. Bibliographies of relevant retrieved studies and recent reviews were also scanned for additional publications. Studies were included if they fulfilled the following criteria: (1) Patients were pathologically verified to have adenocarcinoma of the prostate, (2) the control group consisted of subjects who were men and were free of PCa, (3) the studies were prospective or retrospective case– control studies, and (4) the studies were investigating the association of germline HOXB13 G84E mutation with PCa risk as the main outcome. This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses [2] and Meta-analysis of Observational Studies in Epidemiology [3] guidelines. The effect estimates of choice were odds radio (OR) for dichotomous variables and the corresponding 95% confidence intervals (CIs). The random effects model of DerSimonian and Laird was prespecified for use in overall estimates because of the apriority that studies were from different populations and had different designs (eg, population-based, family-based compared with hospital-based case–control studies). The departure of frequencies from those expected under HardyWeinberg equilibrium was assessed by x goodness-of-fit

Stromal Androgen Receptor Roles in the Development of Normal Prostate, Benign Prostate Hyperplasia, and Prostate Cancer

The prostate is an androgen-sensitive organ that needs proper androgen/androgen receptor (AR) signals for normal development. The progression of prostate diseases, including benign prostate hyperplasia (BPH) and prostate cancer (PCa), also needs proper androgen/AR signals. Tissue recombination studies report that stromal, but not epithelial, AR plays more critical roles via the mesenchymal-epithelial interactions to influence the early process of prostate development. However, in BPH and PCa, much more attention has been focused on epithelial AR roles. However, accumulating evidence indicates that stromal AR is also irreplaceable and plays critical roles in prostate disease progression. Herein, we summarize the roles of stromal AR in the development of normal prostate, BPH, and PCa, with evidence from the recent results of in vitro cell line studies, tissue recombination experiments, and AR knockout animal models. Current evidence suggests that stromal AR may play positive roles to promote BPH and PCa progression, and targeting stromal AR selectively with AR degradation enhancer, ASC-J9, may allow development of better therapies with fewer adverse effects to battle BPH and PCa.

HoxB3 promotes prostate cancer cell progression by transactivating CDCA3

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<0.001) and PSA level (⩾10) (P=0.013). The Kaplan and Meier analysis showed that HoxB3 overexpression predicts poor survival outcome. Overexpression of HoxB3 promotes LNCaP cells proliferation and migration in vitro. Furthermore, depletion of HoxB3 in PC-3 cells decreased the capacity of proliferation in a cell division cycle associated 3 (CDCA3)-dependent manner both in vitro and in vivo. The ChIP analysis indicates that HoxB3 can bind to the CDCA3 promoter region and transactivate the CDCA3 expression. These data suggested that HoxB3 promote prostate cancer progression by upregulating CDCA3 expression and may serve as a potential therapeutic target for human prostate cancer.

Optimal schedule of bacillus calmette-guerin for non-muscle-invasive bladder cancer: a meta-analysis of comparative studies

BackgroundTo explore the necessity of maintenance, efficacy of low-dose and superiority of various combination therapies of Bacillus Calmette-Guérin (BCG) in treatment of superficial bladder cancer (BCa).MethodsComprehensive searches of electronic databases (PubMed, Embase, and the Cochrane Library) were performed, then a systematic review and cumulative meta-analysis of 21 randomized controlled trials (RCTs) and 9 retrospective comparative studies were carried out according to predefined inclusion criteria.ResultsSignificantly better recurrence-free survivals (RFS) were observed respectively in patients who received BCG maintenance, standard-dose and BCG plus epirubicin therapy comparing to those received induction, low-dose and BCG alone. BCG maintenance therapy was also associated with significantly better progression-free survival (PFS), but there were more incidences of adverse events. Pooled results showed no remarkable advantage of BCG combined with Mitomycin C or with interferon α-2b in improving oncologic outcomes. Sensitivity-analyses stratified by study-design and tumor stage led to very similar overall results and often to a decrease of the between-study heterogeneity. Our data confirmed that non-RCT only affected strength rather than direction of the overall results.ConclusionsAll patients with superficial BCa should be encouraged to accept BCG maintenance therapy with standard-dose if well tolerated. Patients can benefit from BCG combined with epirubicin but not from BCG combined with Mitomycin C or interferon α-2b.

Androgen receptor enhances entosis, a non‐apoptotic cell death, through modulation of Rho/ROCK pathway in prostate cancer cells

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.

Targeting fatty acid synthase with ASC-J9 suppresses proliferation and invasion of prostate cancer cells.

Fatty acid synthase (FASN) is the key enzyme for the control of fatty acid synthesis that contributes significantly to the prostate cancer (PCa) progression. It was reported that androgens were able to induce FASN expression in PCa, and addition of the anti‐androgen Casodex might suppress the androgen‐induced FASN expression. However, here we found androgen‐deprivation‐therapy (ADT) with anti‐androgens Bicalutamide (Casodex) or Enzalutamide (MDV3100) had little effect to suppress FASN expression and FASN‐mediated cell growth and invasion during the castration resistant stage when the androgen concentration is 1 nM DHT (dihydrotestosterone). In contrast, the newly developed androgen receptor (AR) degradation enhancer ASC‐J9® suppressed FASN expression and FASN‐mediated cell growth and invasion in various PCa cell lines at 1 nM DHT. Mechanism dissection found ASC‐J9® could suppress significantly the FASN expression and FASN‐mediated PCa progression via the AR‐dependent pathway involving AR→SREBP‐1→FASN signaling in AR‐positive C4‐2 and LNCaP cells and via the AR‐independent pathway involving the modulation of PI3K/AKT→SREBP‐1→FASN signaling in AR‐negative PC‐3 and DU145 cells. Together, these results suggest that FASN is one of the important mechanism why the current ADT eventually fails. ASC‐J9® might represent a new potential therapeutic approach to suppress FASN‐mediated PCa progression via both AR‐dependent and AR‐independent pathways during the castration resistant stage of PCa.

Catalase C-262T polymorphism and risk of prostate cancer: Evidence from meta-analysis

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.

In vivo targeted imaging of early stage prostate cancer using a transferrin based near-infrared fluorescence probe

Transferrin (Tf) stabilized Au nanoclusters were successfully applied in the near-infrared targeted imaging of prostate cancer overexpressing Tf receptor in vivo. The prepared Tf-Au NCs owned the merits of low cytotoxicity, good biocompatibility, and natural metabolism, excellent optical properties in the NIR region and receptor specific cancer targeting ability. In our study, serial imaging in vivo has been performed sequently. The results showed that targeted fluorescence imaging with Tf-Au NCs possessed an amazing capability of detecting the early-stage small tumours, and giving as accurate and reproducible measures of tumour size in mice as external calliper measurements. To our knowledge, this was the first time to study the biomedical application of Tf-Au NCs in vivo via intravenous administration rather than cell experiments or orthotopic injection. These remarkable data could provide direct and factual evidence that Tf-Au NCs are very promising nanoprobes which could be harmlessly and efficiently used for the targeted diagnosis of human tumours in vivo, indicating that the further clinical translation of Tf-Au NCs could be expected.

Targeting estrogen/estrogen receptor alpha enhances Bacillus Calmette-Guérin efficacy in bladder cancer

Recent studies showed the potential linkage of estrogen/estrogen receptor signaling with bladder tumorigenesis, yet detailed mechanisms remain elusive. Here we found a new potential therapy with the combination of Bacillus Calmette Guerin (BCG) and the anti-estrogen ICI 182,780 led to better suppression of bladder cancer (BCa) than BCG alone. Mechanism dissection found ICI 182,780 could promote BCG attachment/internalization to the BCa cells through increased integrin-α5β1 expression and IL-6 release, which may enhance BCG-induced suppression of BCa cell growth via recruiting more monocytes/macrophages to BCa cells and increased TNF-α release. Consistently, in vivo studies found ICI 182,780 could potentiate the anti-BCa effects of BCG in the carcinogen-induced mouse BCa models. Together, these in vitro and in vivo results suggest that combining BCG with anti-estrogen may become a new therapeutic approach with better efficacy to suppress BCa progression and recurrence.

Erratum: OTUB1 de-ubiquitinating enzyme promotes prostate cancer cell invasion in vitro and tumorigenesis in vivo (vol 14, 8, 2015)

Erratum: OTUB1 de-ubiquitinating enzyme promotes prostate cancer cell invasion in vitro and tumorigenesis in vivo (vol 14, 8, 2015)