Fu-Jun Zhao

miR-200b suppresses cell proliferation, migration and enhances chemosensitivity in prostate cancer by regulating Bmi-1.

microRNAs (miRNAs) are a class of small non-coding RNAs that can post-transcriptionally regulate gene expression and play critical roles in many important biological processes. The role of miRNAs in prostate cancer (PCa) development and pathogenesis remains largely unknown. In the present study, we showed that miR-200b was downregulated in clinical prostatic tumors when compared to normal prostate tissue and in advanced PCa cell lines when compared to normal epithelial prostatic cells. Enforced miR-200b expression suppressed PCa cell proliferation and migration and enhanced chemosensitivity to docetaxel by targeting B-cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1). Bmi-1 was detected at higher levels in PCa, and knockdown of Bmi-1 showed similar effects as miR-200b overexpression in PCa cells. Moreover, we confirmed that these effects were correlated with increased levels of E-cadherin and P16 and a reduction in vimentin expression and expression of stem cell markers (CD44 and OCT4). These findings suggest that miR-200b plays vital roles as a tumor-suppressor by targeting Bmi-1 and may be a promising therapeutic target for PCa treatment.

Chimeric molecules facilitate the degradation of androgen receptors and repress the growth of LNCaP cells.

Post-translational degradation of protein plays an important role in cell life. We employed chimeric molecules (dihydrotestosterone-based proteolysis-targeting chimeric molecule [DHT-PROTAC]) to facilitate androgen receptor (AR) degradation via the ubiquitin-proteasome pathway (UPP) and to investigate the role of AR in cell proliferation and viability in androgen-sensitive prostate cancer cells. Western blot analysis and immunohistochemistry were applied to analyse AR levels in LNCaP cells after DHT-PROTAC treatment. Cell counting and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) cell viability assay were used to evaluate cell proliferation and viability after AR elimination in both LNCaP and PC-3 cells. AR was tagged for elimination via the UPP by DHT-PROTAC, and this could be blocked by proteasome inhibitors. Degradation of AR depended on DHT-PROTAC concentration, and either DHT or an ALAPYIP-(arg)(8) peptide could compete with DHT-PROTAC. Inhibition of cell proliferation and decreased viability were observed in LNCaP cells, but not in PC-3 or 786-O cells after DHT-PROTAC treatment. These data indicate that AR elimination is facilitated via the UPP by DHT-PROTAC, and that the growth of LNCaP cells is repressed after AR degradation.

Tumor formation of prostate cancer cells influenced by stromal cells from the transitional or peripheral zones of the normal prostate

This study was designed to investigate the different involvements of prostatic stromal cells from the normal transitional zone (TZ) or peripheral zone (PZ) in the carcinogenesis of prostate cancer (PCa) epithelial cells (PC-3) in vitro and in vivo co-culture models. Ultra-structures and gene expression profiles of primary cultures of human prostatic stromal cells from the normal TZ or PZ were analyzed by electron microscopy and microarray analysis. In vitro and in vivo co-culture models composed of normal TZ or PZ stromal cells and human PCa PC-3 cells were established. We assessed tumor growth and weight in the in vivo nude mice model. There are morphological and ultra-structural differences in stromal cells from TZ and PZ of the normal prostate. In all, 514 differentially expressed genes were selected by microarray analysis; 483 genes were more highly expressed in stromal cells from TZ and 31 were more highly expressed in those from PZ. Co-culture with PZ stromal cells and transforming growth factor-beta1 (TGF-beta1) increased the tumor growth of PC-3 cells in vitro and in vivo, as well as Bcl-2 expression. On the other hand, stromal cells of TZ suppressed PC-3 cell tumor growth in the mouse model. We conclude that ultra-structures and gene expression differ between the stromal cells from TZ or PZ of the normal prostate, and stroma-epithelium interactions from TZ or PZ might be responsible for the distinct zonal localization of prostate tumor formation.

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.

Upregulation of the long non-coding RNA FALEC promotes proliferation and migration of prostate cancer cell lines and predicts prognosis of PCa patients

LncRNAs are aberrantly expressed in various cancer types and were found to be a responsible prognosis biomarker and therapeutic target of many human cancers.

The differential effects of prostate stromal cells derived from different zones on prostate cancer epithelial cells under the action of sex hormones

It is well known that prostate cancer (PCa) occurs predominantly in the peripheral zone (PZ), whereas benign prostatic hyperplasia (BPH) typically develops in the transition zone. To identify possible mechanisms underlying zonal differences, we compared the effects of prostate stromal cells derived from the peripheral zone (PZsc) and the transition zone (TZsc) on a PCa epithelial cell line (PC3) in the presence of sex hormones. First, we observed that androgen receptor (AR) mRNA was more highly expressed in PZsc than TZsc when the cells were treated with dihydrotestosterone (DHT) and β-oestradiol (E2) (P<0.05). By ELISA, we looked for differences in the secretion of peptide growth factors from PZsc and TZsc. We found that keratinocyte growth factor (KGF) secretion increased with increasing concentrations of DHT (P<0.01) and was higher in PZsc than TZsc. Under treatment with DHT plus E2, PZsc secreted more transforming growth factor-β1 (TGF-β1) than TZsc, but this pattern was reversed when the cells were treated with E2 only. With increasing concentrations of DHT, insulin-like growth factor-1 (IGF-1) secretion increased in PZsc but decreased in TZsc. To further characterize the effects of PZsc and TZsc on PC3 cells, we developed a coculture model and performed MTT assays, Western blot analysis and real-time RT-PCR. We found that PZsc promoted PC3 cell proliferation and progression better than TZsc, particularly when treated with 10 nmol l(-1) DHT plus 10 nmol l(-1) E2. In conclusion, our data suggest that PZsc may have a greater capacity to induce PCa development and progression than TZsc via growth factors regulated by sex hormones. These findings provide possible mechanisms underlying zonal differences in prostate diseases, which may aid the search for novel therapeutic targets for PCa.

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.

Thulium laser VapoResection of the prostate versus traditional transurethral resection of the prostate or transurethral plasmakinetic resection of prostate for benign prostatic obstruction: a systematic review and meta-analysis

PurposeTo compare the efficacy and safety of thulium laser VapoResection of the prostate (ThuVaRP) versus standard traditional transurethral resection of the prostate (TURP) or plasmakinetic resection of prostate (PKRP) for benign prostatic obstruction.MethodsSystematic searches were performed in the Medline, EMBASE, the Cochrane Library, Web of Science, and CNKI in December 2017. The outcomes of demographic and clinical characteristics, perioperative variables, complications, and postoperative efficacy including International Prostate Symptom Score (IPSS), quality of life (QoL), maximum flow rate (Qmax), and postvoid residual (PVR) were assessed.Results16 studies were selected in the meta-analysis including nine randomized controlled trials (RCTs) and seven non-RCTs. Among of them, nine studies compared ThuVaRP with PKRP, while seven studies compared ThuVaRP with TURP. It seemed that ThuVaRP needed longer operation time than TURP (WMD = 6.41, 95% CI 1.38–11.44, p = 0.01) and PKRP (WMD = 10.15, 95% CI 5.20–15.10, p < 0.0001). ThuVaRP was associated with less serum hemoglobin decreased, catheterization time, and the length of hospital stay compared with TURP (WMD = − 0.58, 95% CI − 0.77 to 0.38, p < 0.00001; WMD = − 1.89, 95% CI − 2.67 to 1.11, p < 0.00001; WMD = − 2.25, 95% CI − 2.91 to 1.60, p < 0.00001) and PKRP (WMD = − 0.28, 95% CI − 0.46 to 0.10, p = 0.002; WMD = − 1.88, 95% CI − 2.87 to 0.89, p = 0.0002; WMD = − 2.08, 95% CI − 2.63 to 1.54, p<0.00001). According to our assessment, there was no significantly difference in postoperative efficacy.ConclusionsThe pooled data indicated that ThuVaRP had a nearly efficacy to TURP and PKRP based on IPSS, QoL, Qmax, and PVR. Although ThuVaRP was associated with longer operation time, it got distinct superiority on serum hemoglobin decreased, catheterization time, and hospital stay.

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