Bangmin Han

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.

Treatment of Large Impacted Proximal Ureteral Stones: Randomized Comparison of Percutaneous Antegrade Ureterolithotripsy versus Retrograde Ureterolithotripsy

PURPOSE We compared the safety and efficacy of percutaneous antegrade ureterolithotripsy with retrograde ureterolithotripsy for large impacted proximal ureter stones in a prospective randomized manner. MATERIALS AND METHODS A total of 91 patients with large impacted proximal ureteral stones, defined as stones >1 cm in size located between the ureteropelvic junction and the lower border of the fourth lumbar vertebra, were prospectively randomized for antegrade (44) or retrograde (47) ureterolithotripsy. Failure of the procedure (conversion to an open procedure), intraoperative and postoperative morbidity, operative time, hospital stay, stone clearance at discharge home, and follow-up were analyzed in each group. RESULTS The main complications were bleeding (2.3%; 1 of 43) for the antegrade procedure and ureteral injury (2.3%; 1 of 44) for the retrograde procedure. Percutaneous antegrade ureterolithotripsy was associated with longer operative times (75.4+/-11.8 v 30.6+/-7.8 minutes; P<0.001), longer hospital stay (6.3+/-0.5 v 2.1+/-0.4 days; P<0.001), and a longer interval to return to normal activities (7.8+/-0.7 v 2.7+/-0.6 days; P<0.001). Nevertheless, the percutaneous antegrade procedure had a higher stone-free rate both at discharge home (95.3% v 79.5%; P=0.027), and 1 month post-procedure (100% v 86.4%; P=0.026). CONCLUSIONS Percutaneous antegrade ureterolithotripsy is a valuable treatment modality for impacted proximal ureteral calculi larger than 1 cm, and achieves higher stone-free rates than those of retrograde ureteroscopy with holmium:YAG laser lithotripsy. The drawbacks of the antegrade procedure are longer operative time and hospital stay.

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.

2-micrometer continuous wave laser treatment for multiple non-muscle-invasive bladder cancer with intravesical instillation of epirubicin

We have reported the efficacy and safety of 2‐micrometer continuous wave laser resection of non‐muscle‐invasive bladder tumor (NMIVBC) (World J Urology 2010;28:157–161). In this study, we evaluated the use of 2‐micrometer continuous wave laser resection in combination with intravesical instillation of epirubicin for the treatment of multiple NMIVBC.

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.

Low serum testosterone predicts upgrading and upstaging of prostate cancer after radical prostatectomy

Often, pathological Gleason Score (GS) and stage of prostate cancer (PCa) were inconsistent with biopsy GS and clinical stage. However, there were no widely accepted methods predicting upgrading and upstaging PCa. In our study, we investigated the association between serum testosterone and upgrading or upstaging of PCa after radical prostatectomy (RP). We enrolled 167 patients with PCa with biopsy GS ≤6, clinical stage ≤T2c, and prostate-specific antigen (PSA) <10 ng ml−1 from April 2009 to April 2015. Data including age, body mass index, preoperative PSA level, comorbidity, clinical presentation, and preoperative serum total testosterone level were collected. Upgrading occurred in 62 (37.1%) patients, and upstaging occurred in 73 (43.7%) patients. Preoperative testosterone was lower in the upgrading than nonupgrading group (3.72 vs 4.56, P< 0.01). Patients in the upstaging group had lower preoperative testosterone than those in the nonupstaging group (3.84 vs 4.57, P= 0.01). In multivariate logistic regression analysis, as both continuous and categorical variables, low serum testosterone was confirmed to be an independent predictor of pathological upgrading (P = 0.01 and P= 0.01) and upstaging (P = 0.01 and P = 0.02) after RP. We suggest that low serum testosterone (<3 ng ml−1 ) is associated with a high rate of upgrading and upstaging after RP. It is better for surgeons to ensure close monitoring of PSA levels and imaging examination when selecting non-RP treatment, to be cautious in proceeding with nerve-sparing surgery, and to be enthusiastic in performing extended lymph node dissection when selecting RP treatment for patients with low serum testosterone.

Intra-Arterial Chemotherapy for Muscle-Invasive Bladder Cancer Following Transurethral Resection

Purpose: To assess the efficacy of intra-arterial chemotherapy as a bladder-preservation treatment in patients with muscle-invasive bladder cancer (MIBC) following transurethral resection of bladder tumors (TURBT). Materials and Methods: From 2005 June to 2012 November, 46 patients diagnosed with MIBC (clinical stage T2-T3N0M0) underwent three courses of cisplatin-based intra-arterial chemotherapy as a remedial approach for bladder preservation after TURBT. All patients also received intravesical instillation of chemotherapy as a maintenance strategy. Results: All 46 patients completed the treatment with minor complications. The median follow-up time was 34.5 months (range, 8-87 months). Thirty-two patients (69.6%) demonstrated complete response. The three-year and five-year overall survival was 70.65 and 61.23%, and the disease-specific survival over the same periods was 78.03 and 67.62%, respectively. During the entire follow-up period, more than 80% preserved their bladder. Conclusions: Intra-arterial chemotherapy can be performed as a remedial treatment for MIBC patient following TURBT. Combined with TURBT, it offers an option for bladder preservation therapy on patients who are unable or unwilling to undergo radical cystectomy.

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.

Expression of Wnt5a during development of anorectal malformations in a rat model of prenatal exposure to di(n-butyl) phthalate.

Abstract Mounting evidence has indicated the crucial role of Wnt5a in the embryonic development including guts. However, the Wnt5a involvement in the process of anorectal malformations (ARMs) remains unclear. In this study, we examined the expression of Wnt5a during ARMs development in the offspring of di(n-butyl) phthalate (DBP)-treated pregnant rats. During the neonatal period, Wnt5a expression was evaluated in the terminal rectum of ARM offspring, non-ARM littermates and controls. Using real-time polymerase chain reaction (real-time PCR), western-blot analysis and immunohistochemistry approaches, we found a significant decrease of Wnt5a expression in DBP-induced ARMs rats. Collectively, our results demonstrate the aberrant expression of Wnt5a during anorectal development, which suggests that Wnt5a might be involved in DBP-induced ARMs.