Xiaohai Wang

Activated androgen receptor promotes bladder cancer metastasis via Slug mediated epithelial-mesenchymal transition

Androgen receptor (AR) has been indicated to be involved in bladder cancer progression. We showed androgen induced epithelial-mesenchymal transition (EMT) in AR-positive bladder cancer cells and promoted tumor metastasis in xenograft models. We subsequently identified that Slug was the mediator of EMT induced by androgen. Furthermore, upregulation of Slug was due to activation of Wnt/β-catenin signaling in response to androgen. Finally, expression of AR showed strong correlation with loss of E-cadherin, higher expression of Slug and nuclear accumulation of β-catenin in bladder tumor tissues. Taken together, our results suggest AR signaling promotes bladder cancer metastasis through Slug mediated EMT.

Long intragenic non-coding RNA lincRNA-p21 suppresses development of human prostate cancer

Prostate cancer is one of the most frequent malignancies in men, worldwide, although its underlying mechanisms are not fully understood. Long non‐coding RNAs participate in development of human cancers. In this invetsigation, we aimed to study the roles of lincRNA‐p21 in development of human prostate cancer.

Differences in phenotype and gene expression of prostate stromal cells from patients of varying ages and their influence on tumour formation by prostate epithelial cells

Prostate cancer (PCa) is an age-related disease, and the stromal microenvironment plays an important role in prostatic malignant progression. However, the differences in prostate stromal cells present in young and old tissue are still obscure. We established primary cultured stromal cells from normal prostatic peripheral zone (PZ) of donors of varying ages and found that cultured stromal cells from old donors (PZ-old) were more enlarged and polygonal than those from young donors (PZ-young). Furthermore, based on immunocytochemical and ultrastructural analysis, the components of stromal cells changed from a majority of fibroblasts to a mixture of fibroblasts and myofibroblasts with increasing donor age. Using a three-dimensional in vitro culture system, we found that PZ-old stromal cells could enhance the proliferation, migration and invasion of cocultured benign BPH-1 and PC-3 cells. Using an in vivo tissue recombination system, we also found that PZ-old stromal cells are more effective than PZ-young cells in promoting tumour formation by BPH-1 cells of high passage (>100) and PC-3 cells. To probe the possible mechanism of these effects, we performed cDNA microarray analysis and profiled 509 upregulated genes and 188 downregulated genes in PZ-old cells. Among the changed genes, we found genes coding for a subset of paracrine factors that are capable of influencing adjacent epithelial cells; these include hepatocyte growth factor (HGF), fibroblast growth factor 5 (FGF5), insulin-like growth factor 2 (IGF2), insulin-like growth factor-binding protein 4 (IGFBP4), IGFBP5 and matrix metallopeptidase 1 (MMP1). Changes in the expression of these genes were further confirmed by quantitative real-time polymerase chain reaction (PCR), Western blotting and enzyme-linked immunosorbent assays. Overall, our findings indicate that stromal cells from prostate PZ of old donors are more active than similar cells from young donors in promoting the malignant process of adjacent epithelial cells. This finding hints at a new potential strategy for the prevention of PCa.

LincRNA‐p21 suppresses development of human prostate cancer through inhibition of PKM2

Previously, we found that long intergenic non‐coding RNA‐p21 (lincRNA‐p21) inhibited the development of human prostate cancer. However, the underlying molecular mechanisms are poorly understood. Here, we attempted to investigate the downstream targets of lincRNA‐p21 in prostate cancer.

Androgen receptors expressed by prostatic stromal cells obtained from younger versus older males exhibit opposite roles in prostate cancer progression.

Aging is a major risk factor for prostate cancer (PCa), and prostatic stromal cells may also promote PCa progression. Accordingly, stromal cells do not equally promote PCa in older males and younger males. Therefore, it is also possible that the expression of androgen receptors (ARs) by prostatic stromal cells in older versus younger males plays different roles in PCa progression. Using a gene knockdown technique and coculture system, we found that the knockdown of the AR in prostatic stromal cells obtained from younger males could promote the invasiveness and metastasis of cocultured PC3/LNCaP cells in vitro. By contrast, the invasiveness and metastasis of LNCaP cells was inhibited when cocultured with prostatic stromal cells from older males that when AR expression was knocked down. Moreover, after targeting AR expression with small hairpin RNA (shRNA), matrix metalloproteinase (MMP) expression in stromal cells was observed to increase in the younger group, but decreased or remained unchanged in the older group. One exception, however, was observed with MMP9. In vivo, after knocking down AR expression in prostatic stromal cells, the incidence of metastatic lymph nodes was observed to increase in the younger age group, but decreased in the older age group. Together, these data suggest that the AR in prostatic stromal cells played opposite roles in PCa metastasis for older versus younger males. Therefore, collectively, the function of the AR in prostatic stromal cells appears to change with age, and this may account for the increased incidence of PCa in older males.

LIM domain only 2 over-expression in prostate stromal cells facilitates prostate cancer progression through paracrine of Interleukin-11

Mechanisms of stromal-epithelial crosstalk are essential for Prostate cancer (PCa) tumorigenesis and progression. Peripheral zone of the prostate gland possesses a stronger inclination for PCa than transition zone. We previously found a variety of genes that differently expressed among different prostate stromal cells, including LIM domain only 2 (LMO2) which highly expressed in peripheral zone derived stromal cells (PZSCs) and PCa associated fibroblasts (CAFs) compared to transition zone derived stromal cells (TZSCs). Studies on its role in tumors have highlighted LMO2 as an oncogene. Herein, we aim to study the potential mechanisms of stromal LMO2 in promoting PCa progression. The in vitro cells co-culture and in vivo cells recombination revealed that LMO2 over-expressed prostate stromal cells could promote the proliferation and invasiveness of either prostate epithelial or cancer cells. Further protein array screening confirmed that stromal LMO2 stimulated the secretion of Interleukin-11 (IL-11), which could promote proliferation and invasiveness of PCa cells via IL-11 receptor α (IL11Rα) – STAT3 signaling. Moreover, stromal LMO2 over-expression could suppress miR-204-5p which was proven to be a negative regulator of IL-11 expression. Taken together, results of our study demonstrate that prostate stromal LMO2 is capable of stimulating IL-11 secretion and by which activates IL11Rα – STAT3 signaling in PCa cells and then facilitates PCa progression. These results may make stromal LMO2 responsible for zonal characteristic of PCa and as a target for PCa microenvironment-targeted therapy.

The role of urethral pressure profile on treating premature ejaculation by tamsulosin

Society for Sexual Medicine definition. IELT was measured by the patient and his partner using a stop watch. Treatment outcomes were evaluated by IELT, the Clinical Global Impression Change (CGIC groups: “better” or “much better” [B/MB], “slightly better” [SB], and “no change” [NC]), and PE profiles. Ejaculation-related problems were investigated and parameters included were anejaculation, reduced semen volume, and discomfort on orgasm. UPP was performed using a standardized urodynamic technique with Laborie urodynamic unit (Canada). In our study, 27% patients reported B/MB, and the mean average of IELT was prolonged (from 0.63 to 3.92 min), and about 30% of patients reported SB, and the mean average of IELT was prolonged (from 0.71 to 1.72 min). Ejaculation control, satisfaction with sexual intercourse, and ejaculation-related personal distress were all significantly improved in 30% patients. Recently, eight PE patients were treated with silodosin, which is a highly selective α1A-adrenergic blocker. Silodosin (4 mg) given 2 h before sexual intercourse, prolonged IELT significantly (from 3.4 to 10.1 min), and all patients reported “B” (MB) or SB for their own PE problem compared with pretreatment condition in the CGIC.8 Several researchers have reported their experience with the selective α1-adrenergic blockers, alfuzosin and terazosin in the treatment of PE. However, those studies were limited by the use of subjective study end points of patient impression related to change and sexual satisfaction, and they did not evaluate actual ejaculatory latency. There were four UPP parameters adopted (Figure 1), including maximal urethral closure pressure (MUCP), prostatic length (PL), functional profile length (FPL), and prostatic plateau area (PPA). Interestingly, UPP parameters (MUCP, PL and PPA) were significantly lower in group B/MB than in group NC or group SB, which indicated that tamsulosin was prone to be effective in treating PE patients with lower MUCP, lower PL, or lower PPA. For the first time, our present study indicated that treating PE by tamsulosin was more effective in 73% patients with low PPA (PPA ≤48 cm cmH2O) than in 25% patients with high PPA (PPA > 48 cm cmH2O) (x = 4.960, P = 0.039). International Prostate Symptom Score (baseline and after treatment) showed no significant difference between low PPA group and high PPA group (Table 1). The results suggest that ejaculation threshold after the treatment by tamsulosin is higher in patients with low PPA than in patients with high PPA. About 30% of patients received tamsulosin and experienced ejaculatory dysfunction.9 Recent study was undertaken to determine the impact of tamsulosin (0.2 mg once daily for 12 weeks) on ejaculatory function. The overall incidence of ejaculatory dysfunction Dear Editor, I am Dr. Hui-Rong Chen, from the Department of Urology in Shanghai First People’s Hospital at Shanghai Jiao Tong University, Shanghai, China. Premature ejaculation (PE) is a common sexual dysfunction, affecting approximately 20%–30% of sexually active men. According to intravaginal ejaculatory latency time (IELT) of 1 min, the incidence is approximately 1%–3%.1 PE is significantly associated with many personal and negative consequences, such as distress, frustration, and avoidance of sexual intimacy due to the inability of successful delayed ejaculation. α1-adrenergic blockers were effective in delaying ejaculation in approximately 50%–67% of the cases.2,3 Recently, abnormal ejaculation, an adverse infrequent side effect associated with the use of α1A-adrenergic blockers such as silodosin or tamsulosin, has drawn significant attention. Clinical studies suggested that this represents a relative anejaculation rather than a retrograde ejaculation.4,5 We present here the study to investigate the role of urethral pressure profile (UPP) on treating PE by tamsulosin. The effects of α1-adrenergic blockers (tamsulosin, silodosin, alfuzosin, and naftopidil) on noradrenaline-induced contractions were studied in rat isolated seminal vesicles, vas deferens, bladder trigone, and prostate. All α1-adrenergic blockers dose-dependently decreased the number of copulatory plugs and inhibited the phenylephrine-induced increase in intraurethral pressure.6 In vivo study suggested that α1-adrenergic blockers (alfuzosin, naftopidil, prazosin, silodosin, and tamsulosin) inhibit contraction of both the posterior urethra and the vas deferens in male dogs, and they have higher tissue selectivity for the vas deferens than for the posterior urethra. The imbalance between intraurethral pressure in the prostatic urethra and intraluminal pressure in the vas deferens may contribute to abnormal ejaculation.7 The intraluminal pressure in vas deferens could not be measured clinically with the present study equipment. UPP was used to determine the intraurethral pressure in the prostatic urethra, which may help to assess partly the imbalance between intraurethral pressure in the prostatic urethra and intraluminal pressure in the vas deferens. Twenty-three patients suffering from PE and mild lower urinary tract symptoms (LUTS) were treated with tamsulosin 0.4 mg orally daily for 4 weeks. PE criteria were identified according to 2008 International The role of urethral pressure profile on treating premature ejaculation by tamsulosin

Endothelial cells promote metastasis of prostate cancer by enhancing autophagy

BackgroundProstate cancer is one of the most common malignancies. Increasing evidence suggested that endothelial cells may contribute to prostate cancer progression and metastasis. Most recently, autophagy has been proposed to plays a significant role in tumorigenesis and metastasis. Also, it is reported that downregulation of androgen receptor (AR) induces autophagy in prostate cancer cells. However, the underlying mechanisms remain unclear. Here, we aim to explore the role and mechanisms of endothelial cell in prostate cancer progression.MethodsThe coculture system was established to test the effect of endothelial cells on prostate cancer cells. We performed antibody array and ELISA were used to profile the cytokine expression pattern of endothelial cells in supernatant. Western blot and RT-PCR were used to determine the mechanism by endothelial cells to promote invasion ability of prostate cancer cells. Maraviroc and chloroquine were used to block the CCL5/CCR5 and autophagy pathway respectively. Orthotopic xenograft mouse models and drug treatment study were conducted to determine the role of endothelial cells in promoting metastatic potential in vivo.ResultsWe use CPRC prostate cancer model and demonstrate that endothelial cells secrete large amount of CCL5 and induces autophagy by suppressing AR expression in prostate cancer cell lines. Consequently, elevated autophagy accelerates focal adhesions proteins disassembly and promoted prostate cancer invasion. Inhibition of both CCL5/CCR5 signaling and autophagy significantly reduces metastasis in vivo.ConclusionsTogether, our data establish the function for endothelial cells in tumor metastasis and propose new drug target for mCRPC.

Deregulation of ATG9A by impaired AR signaling induces autophagy in prostate stromal fibroblasts and promotes BPH progression

The activation of androgen receptor (AR) signaling plays an essential role in both prostate stromal cells and epithelial cells during the development of benign prostatic hyperplasia (BPH). Here we demonstrated that androgen ablation after 5α-reductase inhibitor (5-ARI) treatment induced autophagy in prostate stromal fibroblasts inhibiting cell apoptosis. In addition, we found that ATG9A expression was increased after androgen ablation, which facilitated autophagic flux development. Knockdown of ATG9A not only inhibited autophagy notably in prostate stromal fibroblasts, but also reduced the volumes of prostate stromal fibroblast and epithelial cell recombinant grafts in nude mice. In conclusion, our findings suggested that ATG9A upregulation after long-term 5-ARI treatment constitutes a possible mechanism of BPH progression. Thus, combined treatment with 5-ARI and autophagy inhibitory agents would reduce the risk of BPH progression.

The androgen receptor plays different roles in macrophage-induced proliferation in prostate stromal cells between transitional and peripheral zones of benign prostatic hypertrophy

: Macrophages play a critical role in the process of excessive stromal proliferation of benign prostatic hyperplasia (BPH). In our previous study, we used a BPH mouse model to elucidate a potential mechanism whereby macrophage infiltration promotes stromal cell proliferation in the prostate via the androgen receptor (AR)/inflammatory cytokine CCL3-dependent pathway. In our present study, we used the co-culture system of human macrophages and various prostatic zone stromal cells to further demonstrate that infiltrating macrophages promote prostatic stromal cell proliferation through stromal AR-dependent pathways, and we show that the stroma of TZ and PZ respond to macrophages differently because of differences in stromal AR signaling; this could possibly be one of the key pathways for stromal expansion during BPH development and progression. We hypothesize that AR and different downstream inflammatory mediators between TZ and PZ could serve as potential targets for the future design of therapeutic agents for BPH and our results provide significant insights into the search for targeted therapeutic approaches to battle BPH.