ATXN3 promotes prostate cancer progression by stabilizing YAP.

BACKGROUND: Prostate cancer (PC) is the most common neoplasm and is the second leading cause of cancer-related deaths in men worldwide. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. YAP is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal YAP expression in PC remains to be characterized. METHODS: Western blot was used to measure the protein expression of ATXN3 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect cell viability; transwell invasion assay was used to measure the invasion ability of PC. The xeno-graft tumor model was used for in vivo study. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between YAP and ATXN3. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. RESULTS: In the present study, we identified ATXN3, a DUB enzyme in the ubiquitin-specific proteases family, as a bona fide deubiquitylase of YAP in PC. ATXN3 was shown to interact with, deubiquitylate, and stabilize YAP in a deubiquitylation activity-dependent manner. Depletion of ATXN3 decreased the YAP protein level and the expression of YAP/TEAD target genes in PC, including CTGF, ANKRD1 and CYR61. Further mechanistic study revealed that the Josephin domain of ATXN3 interacted with the WW domain of YAP. ATXN3 stabilized YAP protein via inhibiting K48-specific poly-ubiquitination process on YAP protein. In addition, ATXN3 depletion significantly decreased PC cell proliferation, invasion and stem-like properties. The effects induced by ATXN3 depletion could be rescued by further YAP overexpression. CONCLUSIONS: In general, our findings establish a previously undocumented catalytic role for ATXN3 as a deubiquitinating enzyme of YAP and provides a possible target for the therapy of PC. Video Abstract.

[Double-channel expansion of the subcutaneous lower abdominal tunnel for sequential inguinal lymph node dissection in penile cancer - Report of six cases].

OBJECTIVE: To investigate the safety and efficacy of the two-channel dilatation procedure for subcutaneous tunneling in the lower abdomen during pelvic lymph node dissection for penile cancer. METHODS: A retrospective analysis was conducted on the clinical data of 6 patients treated from January 2020 to December 2022 using the dual-channel expansion technique for penile cancer lymph node dissection. RESULTS: All 6 cases ( 12 sides) successfully underwent prophylactic inguinal lymph node dissection. The average laparoscopic dissection time was ( 82.50 ± 12.08) minutes per side, with an average blood loss of （28.33 ± 10.95） ml. The number of lymph nodes dissected was （11.16 ± 1.02） for the superficial group and ( 0.67 ± 0.74 ) for the deep group. Postoperative pathology was negative in all cases. The average postoperative hospital stay was （7.33 ± 1.60 ） days, with a catheter removal time of （12.00 ± 2.06）days. Postoperative complications included abnormal skin sensations in 5 sides, lower limb edema in 3 sides, lymphedema in 3 sides, and cellulitis in 1 side. During a follow-up period of （20.60 ± 12.51）months, there were no instances of tumor recurrence or metastasis in the inguinal region among the patients. CONCLUSION: The dual-channel expansion technique for inguinal lymph node dissection via a subcutaneous tunnel is a safe and feasible treatment for penile cancer. It has a low complication rate, allows for thorough dissection of inguinal lymph nodes, and offers advantages in terms of surgical time.

Oncogenic GBX2 promotes the malignant behaviors of bladder cancer cells by binding to the ITGA5 promoter and activating its transcription.

In bladder cancer patients, metastasis after surgical resection and serious adverse reactions brought by cisplatin-based systemic chemotherapy make it urgent to explore novel therapeutic methods for improving the clinical outcomes of patients with unsuccessful first-line chemotherapy and disease progression. In this study, GBX2 has been recognized as a differentially expressed transcriptional factor between bladder cases with response to treatment and progressive disease based on online expression profile analysis. Higher GBX2 expression was correlated with poorer OS, DSS, and PFS in bladder cancer patients. GBX2 co-expressed genes were enriched in ECM regulation. ITGA5 was positively correlated with GBX2. GBX2 and ITGA5 were notably elevated in bladder cancer cells. GBX2 and ITGA5 similarly affected bladder cancer cell phenotypes via facilitating cell viability, migration, and invasion. By binding to the promoter region of ITGA5, GBX2 activated ITGA5 transcription, upregulating ITGA5 expression. In bladder cancer cells co-transfected with sh-GBX2 and ITGA5 oe, the inhibitory effects of GBX2 knockdown on bladder cancer cell malignant behaviors were partially eliminated by ITGA5 overexpression. In conclusion, GBX2 and ITGA5 serve as oncogenic factors, promoting the viability, migration, and invasion of bladder cancer cells. GBX2 exerts its functions by targeting the ITGA5 promoter region to activate ITGA5 transcription.

SLC26A4 correlates with homologous recombination deficiency and patient prognosis in prostate cancer.

BACKGROUND: Homologous recombination deficiency (HRD) is closely associated with patient prognosis and treatment options in prostate cancer (PCa). However, there is a lack of quantitative indicators related to HRD to predict the prognosis of PCa accurately. METHODS: We screened HRD-related genes based on the HRD scores and constructed an HRD cluster system to explore different clinicopathological, genomic, and immunogenomic patterns among the clusters. A risk signature, HRDscore, was established and evaluated by multivariate Cox regression analysis. We noticed that SLC26A4, a model gene, demonstrated unique potential to predict prognosis and HRD in PCa. Multi-omics analysis was conducted to explore its role in PCa, and the results were validated by qRT-PCR and immunohistochemistry. RESULTS: Three HRD clusters were identified with significant differences in patient prognosis, clinicopathological characteristics, biological pathways, immune infiltration characteristics, and regulation of immunomodulators. Further analyses revealed that the constructed HRDscore system was an independent prognostic factor of PCa patients with good stability. Finally, we identified a single gene, SLC26A4, which significantly correlated with prognosis in three independent cohorts. Importantly, SLC26A4 was confirmed to distinguish PCa (AUC for mRNA 0.845; AUC for immunohistochemistry score 0.769) and HRD (AUC for mRNA 0.911; AUC for immunohistochemistry score 0.689) at both RNA and protein levels in our cohort. CONCLUSION: This study introduces HRDscore to quantify the HRD pattern of individual PCa patients. Meanwhile, SLC26A4 is a novel biomarker and can reasonably predict the prognosis and HRD in PCa.

Dual-tracer PET/CT-targeted, mpMRI-targeted, systematic biopsy, and combined biopsy for the diagnosis of prostate cancer: a pilot study.

PURPOSE: Growing evidence proved the efficacy of multi-parametric MRI (mpMRI) and prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-guided targeted biopsy (TB) in prostate cancer (PCa) diagnosis, but there is no direct comparison between mpMRI-TB and PSMA PET/CT-TB. Gastrin-releasing peptide receptor (GRPR) is highly expressed in PCa, which can compensate for the unstable expression of PSMA in PCa. Therefore, we designed a study to compare the efficiency of mpMRI-TB, dual-tracer (GRPR and PSMA) PET/CT-TB, systematic biopsy, and combined biopsy for the diagnosis of prostate cancer. METHODS: One hundred twelve suspicious PCa patients were enrolled from September 2020 to June 2021. Patients with anyone of positive dual-tracer PET/CT or mpMRI underwent TB, and all enrolled patients underwent systematic biopsy (SB) after TB. The primary outcome was the detection rates of PCa in different biopsy strategies. Secondary outcomes were the performance of three imaging methods, omission diagnostic rates, and upgrading and downgrading of biopsy samples relative to those of prostatectomy specimens in different biopsy strategies. McNemar's tests and Bonferroni correction in multiple comparisons were used to compare the primary and secondary outcomes. RESULTS: In 112 men, clinically significant PCa (grade group[GG] ≥ 2) accounted for 34.82% (39/112), and nonclinically significant PCa (GG = 1) accounted for 4.46% (5/112). 68 Ga-PSMA PET/CT-TB achieved higher PCa detection rate (69.77%) and positive ratio of biopsy cores (0.44) compared with SB (39.29% and 0.12) and mpMRI-TB (36.14% and 0.23), respectively (P < 0.005). Dual-tracer PET/CT screen out patients for avoiding 52.67% (59/112) unnecessary biopsy, whereas dual-tracer PET/CT-TB plus SB achieved high detection rate (77.36%) without misdiagnosis of csPCa. CONCLUSION: Dual-tracer PET/CT might screen patients for avoiding unnecessary biopsy. Dual-tracer PET/CT-TB plus SB might be a more effective and promising strategy for the definite diagnosis of clinically significant PCa than mpMRI-TB.

Androgen receptor-regulated circFNTA activates KRAS signaling to promote bladder cancer invasion.

The androgen receptor (AR) has been linked to bladder cancer (BCa) progression, but if this involves circular RNAs (circRNAs) remains unclear. Here, we find that AR alters the levels of circRNA-FNTA (circFNTA) to increase BCa cell invasion and chemo-resistance. Mechanistically, AR represses the RNA editing gene ADAR2 via direct binding to its 5' promoter region to increase circFNTA levels, which then sponges the microRNA miR-370-3p to increase the expression of its host gene FNTA. This AR-mediated ADAR2/circFNTA/miR-370-3p/FNTA pathway then activates KRAS signaling to alter BCa cell invasion and chemo-sensitivity to cisplatin. A clinical BCa sample survey shows that circFNTA expression is elevated in BCa tissues, and results from a BCa mouse model indicate that depletion of circFNTA leads to the suppression of BCa metastases and increased cisplatin chemo-sensitivity. Together, based on our results using multiple BCa cell lines and an in vivo mouse model we suggest that targeting this newly identified AR/ADAR2/circFNTA/miR-370-3p/FNTA/KRAS axis may lead to the development of therapies to suppress BCa metastasis and to increase its chemo-sensitivity.

circ_100984-miR-432-3p axis regulated c-Jun/YBX-1/ß-catenin feedback loop promotes bladder cancer progression.

Bladder cancer (BC) is one of the most commonly diagnosed cancers globally. Recently, circular RNAs (circRNAs) have been revealed to participate in BC progression with diverse mechanisms. However, mechanisms of circ_100984 in BC have not been determined. Here, we found that circ_100984 and YBX-1 were high presented, while miR-432-3p was low presented in BC. Silencing of circ_100984 and YBX-1 repressed BC tumor growth, migration, and invasion in vitro and in vivo. Mechanistically, we revealed that circ_100984 served as a competing endogenous RNA that sponged miR-432-3p to indirectly regulate YBX-1 and epithelial-mesenchymal transition (EMT)-related molecules. Moreover, we confirmed that YBX-1 or c-Jun acted as a transcription regulatory factor for ß-catenin or YBX-1, respectively, in BC cells. Knockdown of YBX-1 inhibited the expression of ß-catenin and c-Jun, whereas downregulated c-Jun inversely repressed the expression of YBX-1 and ß-catenin. Our results suggested that circ_100984-miR-432-3p axis regulated c-Jun/YBX-1/ß-catenin feedback loop promotes BC progression, providing a potential therapeutic axis for BC progression.

5mC regulator-mediated molecular subtypes depict the hallmarks of the tumor microenvironment and guide precision medicine in bladder cancer.

BACKGROUND: Depicting the heterogeneity and functional characteristics of the tumor microenvironment (TME) is necessary to achieve precision medicine for bladder cancer (BLCA). Although classical molecular subtypes effectively reflect TME heterogeneity and characteristics, their clinical application is limited by several issues. METHODS: In this study, we integrated the Xiangya cohort and multiple external BLCA cohorts to develop a novel 5-methylcytosine (5mC) regulator-mediated molecular subtype system and a corresponding quantitative indicator, the 5mC score. Unsupervised clustering was performed to identify novel 5mC regulator-mediated molecular subtypes. The principal component analysis was applied to calculate the 5mC score. Then, we correlated the 5mC clusters (5mC score) with classical molecular subtypes, immunophenotypes, clinical outcomes, and therapeutic opportunities in BLCA. Finally, we performed pancancer analyses on the 5mC score. RESULTS: Two 5mC clusters, including 5mC cluster 1 and cluster 2, were identified. These novel 5mC clusters (5mC score) could accurately predict classical molecular subtypes, immunophenotypes, prognosis, and therapeutic opportunities of BLCA. 5mC cluster 1 (high 5mC score) indicated a luminal subtype and noninflamed phenotype, characterized by lower anticancer immunity but better prognosis. Moreover, 5mC cluster 1 (high 5mC score) predicted low sensitivity to cancer immunotherapy, neoadjuvant chemotherapy, and radiotherapy, but high sensitivity to antiangiogenic therapy and targeted therapies, such as blocking the ß-catenin, FGFR3, and PPAR-γ pathways. CONCLUSIONS: The novel 5mC regulator-based subtype system reflects many aspects of BLCA biology and provides new insights into precision medicine in BLCA. Furthermore, the 5mC score may be a generalizable predictor of immunotherapy response and prognosis in pancancers.

The VIM-AS1/miR-655/ZEB1 axis modulates bladder cancer cell metastasis by regulating epithelial-mesenchymal transition.

BACKGROUND: Invasive bladder tumors cause a worse prognosis in patients and remain a clinical challenge. Epithelial-mesenchymal transition (EMT) is associated with bladder cancer metastasis. In the present research, we attempted to demonstrate a novel mechanism by which a long noncoding RNA (lncRNA)-miRNA-mRNA axis regulates EMT and metastasis in bladder cancer. METHODS: Immunofluorescence (IF) staining was used to detect Vimentin expression. The protein expression of ZEB1, Vimentin, E-cadherin, and Snail was investigated by using immunoblotting assays. Transwell assays were performed to detect the invasive capacity of bladder cancer cells. A wound healing assay was used to measure the migratory capacity of bladder cancer cells. RESULTS: Herein, we identified lncRNA VIM-AS1 as a highly- expressed lncRNA in bladder cancer, especially in metastatic bladder cancer tissues and high-metastatic bladder cancer cell lines. By acting as a ceRNA for miR-655, VIM-AS1 competed with ZEB1 for miR-655 binding, therefore eliminating the miR-655-mediated suppression of ZEB1, finally promoting EMT in both high- and low-metastatic bladder cancer cells and enhancing cancer cell metastasis. CONCLUSIONS: In conclusion, the VIM-AS1/miR-655/ZEB1 axis might be a promising target for improving bladder cancer metastasis via an EMT-related mechanism.

Silencing of MEG3 attenuated the role of lipopolysaccharides by modulating the miR-93-5p/PTEN pathway in Leydig cells.

BACKGROUND: Leydig cells reflect the activation of inflammation, decrease of androgen production, inhibition of cell growth and promotion of cell apoptosis under orchitis. Maternally expressed gene 3 (MEG3) exerts a crucial role in various human diseases, but under orchitis, the role and underlying molecular mechanism of MEG3 in Leydig cells remain unclear. METHODS: Lipofectamine 2000 was used for the cell transfections. qPCR and western blots assay were applied to assess the gene expression. ELISA assay was used to measure the TNFα, IL6 and testosterone secretion. CCK8 and EdU assay was employ to test the cell viability and proliferation respectively. Luciferase reporter and RIP assay were introduced to detect the binding of miR-93-5p with MEG3 and PTEN. RESULTS: Lipopolysaccharides (LPS) induced TNFα and IL6 secretion, lowered testosterone production, inhibited cell viability and proliferation, and induced cell apoptosis in Leydig cells. MEG3 was upregulated in Leydig cells treated with LPS and that knockdown of MEG3 inhibited the role of LPS in Leydig cells. MEG3 absorbed miR-93-5p and that suppression of miR-93-5p restored the role of silenced MEG3 in Leydig cells under LPS treatment. miR-93-5p inhibited PTEN expression and that over-expressed PTEN alleviated the effect of miR-93-5p in Leydig cells treated with LPS. LPS activated the MEG3/miR-93-5p/PTEN signalling pathway in Leydig cells. CONCLUSIONS: This study revealed that MEG3 serves as a molecular sponge to absorb miR-93-5p, thus leading to elevation of PTEN expression in Leydig cells under LPS treatment, offering a theoretical basis on which to establish potential new treatment strategies for orchitis.

Neoadjuvant Chemotherapy Benefits Survival in High-Grade Upper Tract Urothelial Carcinoma: A Propensity Score-Based Analysis.

BACKGROUND: To evaluate the benefit of neoadjuvant chemotherapy (NAC) for survival in high-grade upper tract urothelial carcinoma (UTUC), a propensity score-based analysis was performed with high-grade UTUC patients from multiple urologic centers. METHODS: From three urologic centers, 48 high-grade UTUC patients who received chemotherapy followed by surgery (NAC group) and 72 high-grade UTUC patients who underwent initial surgery (no-NAC group) were involved in a propensity score-based analysis. After propensity score-based (1:1) matching, 37 patients receiving NAC and 37 patients not receiving NAC were followed. RESULTS: The patients who received NAC had improved disease-free survival (DFS) and overall survival (OS), with a 3-year DFS rate of 78.4% and an OS rate of 86.5% versus a 3-year DFS rate of 51.4% and an OS rate of 62.2% for those treated with initial surgery (P = 0.018 and P = 0.02, respectively). In the multivariate analysis, the NAC group had a lower risk for mortality [DFS hazard ratio (HR) 0.25; 95% confidence interval (CI) 0.10-0.62; P = 0.003; OS HR 0.22; 95% CI 0.085-0.57; P = 0.002]. The analysis of patient survival in matched subgroups showed that NAC was beneficial in terms of the 3-year DFS for the group with a cT of 3 or higher (DFS HR 0.37; 95% CI 0.14-0.94; P = 0.036) and the group that had tumor with hydronephrosis (DFS HR 0.31; 95% CI 0.11-0.87; P = 0.026). CONCLUSION: The study showed that NAC may be considered as an effective addition to surgery for the treatment in high-grade UTUC patients.

Depression and perceived stress among the medical residents under the "unified double-track" training systems. / "双轨合一"培训模式下住院医师的抑郁症状和知觉压力.

OBJECTIVES: It is an important reform for medical education in China to combine professional postgraduate training with standardized resident training. This study aims to evaluate the depression and perceived stress in postgraduate students of clinical medicine and residents from society and to determine the relation between depression and perceived stress in medical residents. METHODS: Chinese Perceived Stress Scale (CPSS) and Self-Rating Depression Scale (SDS) were applied to 330 residents (including 235 postgraduate students of clinical medicine and 95 residents from society) from a Class-A Grade-3 genernal hospital in Hunan Province to evaluate and compare the depression and perceived stress in postgraduate students of clinical medicine and residents from society. Pearson correlation analysis was performed to assess the association between depression and perceived stress. Stress resources between 2 groups of residents were observed and compared. RESULTS: Of the 235 postgraduate students of clinical medicine, 148 (63.0%) showed depression and 162 (68.9%) showed elevated perceived stress. Main stress resources were academic pressure, scientific research pressure, and employment pressure. Of the 95 residents from society, 52 (54.7%) showed depression and 58 (61.1%) showed elevated perceived stress. Main stress resources were economic stress, employment pressure, and academic pressure. The scores of CPSS and SDS were significantly higher in postgraduate students of clinical medicine than those in residents from society (t=2.110, P=0.036; t=2.810, P=0.005, respectively), while gender showed no difference in the scores of CPSS and SDS (t=-0.968, P=0.334; t=0.462, P=0.644, respectively). There was a significant positive correlation between depression and perceived stress (r=0.854, P<0.001). CONCLUSIONS: Residents (including postgraduate students of clinical medicine and residents from society) possess depression and elevated perceived stress with positive correlation. The postgraduate students of clinical medicine show higher level of depression and perceived stress than the residents from society under the "unified double-track" training system.

ISYNA1 is overexpressed in bladder carcinoma and regulates cell proliferation and apoptosis.

BACKGROUND: Bladder cancer (BCa) is one of the most common urological malignancies. While Inositol-3-phosphate synthase 1 (ISYNA1) expression and function were largely unknown in BCa. We aimed to study the expression and role of ISYNA1 in bladder cancer and investigate its potential mechanisms via ingenuity pathway analysis (IPA). METHODS: ISYNA1 expression was quantified by qRT-PCR in bladder cancer cell lines as well as normal urothelial cell line. Knocking down ISYNA1 gene in BCa T24 cells was achieved by shRNA lentivirus transfection. MTT and Celigo assay were used to assess cell proliferation. Flow cytometry was applied to test cell cycle and apoptosis. In addition, IPA was performed using PrimeView™ Human Gene Expression Array. Imunohistochemistry (IHC) was performed in BCa patient tissue microarray to verify the association between ISYNA1 expression and patients' clinicopathological features. RESULTS: ISYNA1 was significantly upregulated in BCa samples vs. para-tumor tissues. Higher expression were significantly associated with tumor T stage and lymph node metastasis of bladder cancer patients. Similarly, it was elevated in BCa cell lines (5637 and T24) compared with SVHUC cells. Knocking down ISYNA1 significantly decreased proliferation, induced apoptosis and cell cycle arrest in T24 cells. Furthermore, IPA indicated that ISYNA1 was an important regulatory factors and related networks were involved in multiple functional processes. CONCLUSION: Taken together, current study suggest ISYNA1 promotes proliferation and inhibit apoptosis in bladder cancer cells, and its expression correlated with BCa patients' clinicopathological features. Thus, ISYNA1 may serve as a potential biomarker and therapeutic target for BCa patients.

Tamsulosin as a Medical Expulsive Therapy for Ureteral Stones: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

PURPOSE: Tamsulosin is widely administered as a medical expulsive therapy to facilitate stone passage in patients with ureteral calculi. Recently several large, multicenter, randomized controlled trials revealed conflicting results, which led to considerable uncertainty about the efficacy of tamsulosin in the management of ureteral stones. The objective of this systematic review and meta-analysis was to evaluate the efficacy and safety of tamsulosin in the management of ureteral stones. MATERIALS AND METHODS: We searched MEDLINE®, Embase®, Web of Knowledge, Google Scholar™ and the Cochrane Central Search Library databases up to June 2018. Two reviewers independently evaluated eligible randomized controlled trials of the efficacy of tamsulosin to treat ureteral stones. Study quality was assessed with the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. Subgroup analyses were performed to explore heterogeneity. RESULTS: Included in study were 56 randomized controlled trials in a total of 9,395 patients. The observed treatment effect indicated that tamsulosin was associated with a higher stone expulsion rate (RR 1.44, 95% CI 1.35-1.55, p <0.01), a shorter stone expulsion time (weighted mean difference -0.73, 95% CI -1.00--0.45, p <0.01), a lesser incidence of ureteral colic (weighted mean difference -0.81, 95% CI -1.24--0.39, p <0.01) and fewer incidences of requiring subsequent intervention (RR 0.68, 95% CI 0.50-0.93, p = 0.017). Treatment with tamsulosin did not differ from a control group in the overall incidence of side effects (RR 1.14, 95% CI 0.86-1.51, p = 0.36). On subgroup analysis we observed a significant benefit in the stone expulsion rate for tamsulosin among patients with stones greater than 5 mm (RR 1.44, 95% CI 1.22-1.68, p <0.01) but no effect for stones 5 mm or less (RR 1.08, 95% CI 0.99-1.68, p <0.01). CONCLUSIONS: Our current meta-analysis results indicate that tamsulosin is effective and relatively safe in patients with ureteral stone as a medical expulsive therapy to facilitate stone passage. It is suggested to administer it selectively in patients with 5 to 10 mm ureteral stones.

Forkhead Box R2 Knockdown Decreases Chemoresistance to Cisplatin via MYC Pathway in Bladder Cancer.

BACKGROUND Bladder cancer is a very common urological cancer globally, and cisplatin- or gemcitabine-based chemotherapy is essential for advanced bladder cancer patients. Many patients with bladder cancer have a relatively poor response to chemotherapy, leading to failure of clinical treatment. We mined the GSE77883 GEO dataset, identifying FoxR2 as being a significantly upregulated gene in T24 chemoresistant cells. Herein, we assessed how FoxR2 functions in bladder cancer cell chemoresistance. MATERIAL AND METHODS Cisplatin-resistant T24 (T24/DDP) cells were constructed by administering increasing concentrations of cisplatin, and differences in expression of FoxR2 were examined in T24/DDP and T24 cells. FoxR2 loss- and gain-of-function cells models were established in T24/DDP and T24 cells, respectively. Cell survival, clone formation, cell cycle, and cell apoptosis were assessed, and the MYC pathway was verified. RESULTS FoxR2 was significantly upregulated in T24/DDP cells compared to T24 cells. Knockdown of FoxR2 in T24/DDP cells, survival rate, and clone formation were decreased, G1/S phase transition was suppressed, and cell apoptosis was promoted. These results were reversed by restoration of FoxR2 levels in T24 cells. We found that FoxR2 knockdown enhanced sensitivity to cisplatin, whereas MYC overexpression antagonized chemosensitivity in T24/DDP cells. CONCLUSIONS FoxR2 knockdown decreases chemoresistance to cisplatin via the MYC pathway in bladder cancer cells, and this may be a target for overcoming chemoresistance in bladder cancer.

LncRNA-MALAT1 mediates cisplatin resistance via miR-101-3p/VEGF-C pathway in bladder cancer.

Cisplatin (CDDP)-based chemotherapy is a standard strategy for the clinical treatment of patients with bladder cancer (BC). However, the anti-tumor efficacy of cisplatin is affected by multiple chemoresistance with complex molecular mechanisms. Recent evidence highlights the crucial regulatory roles of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in the progression of cancers and development of drug resistance. However, the roles and underlying molecular mechanisms of MALAT1 in cisplatin resistance of the BC cells remain largely unclear. In this study, we firstly demonstrated that MALAT1 expression was up-regulated in the BC tissues compared to the normal adjacent tissues and elevated in the cancer cells compared to the epithelial immortalized cells. Secondly, we found that suppression of MALAT1 enhanced the chemotherapeutic drug sensitivity and inhibited the cisplatin resistance of the BC cells. Thirdly, we showed that MALAT1 affected the cisplatin resistance of the BC cells via regulating the miR-101-3p/VEGF-C pathway. In summary, this study demonstrates that MALAT1, miR-101-3p and VEGF-C form a regulatory axis to affect the chemo-resistance of BC cells to CDDP, and provides novel potential targets for treatment of BC.

Prognostic factors in patients with penile cancer after surgical management.

PURPOSE: To examine the possible prognostic factors in patients with penile cancer after surgical management and to identify the independent predictive factors of the prognosis. MATERIALS AND METHODS: Clinical data of 135 patients with penile cancer who underwent surgical management in two medical centers were collected. Follow-up data were available for 103 patients. Possible prognostic factors including patient's age; smoking or not; course of disease; phimosis or not; type of surgery; tumor stage; nodal stage; tumor grade and pathological lymph nodes metastasis were retrospectively analyzed by univariate and multivariate analyses with Cox regression. RESULTS: Five-year cancer-specific survival (CSS) and 1-year CSS were 88.5 and 98.1%, respectively. Univariate Cox analysis revealed that nodal stage and pathological lymph nodes metastasis were significant prognostic factors. Multivariate Cox analysis revealed pathological lymph nodes metastasis was the independent predictive factor of the prognosis. CONCLUSION: Pathological lymph nodes metastasis is the independent predictive factor worsening the prognosis in patients with penile cancer.

Localized chromophobe renal cell carcinoma: preoperative imaging judgment and laparoscopic simple enucleation for treatment.

OBJECTIVE: To evaluate the preoperative imaging manifestation and therapeutic effect of laparoscopic simple enucleation (SE) for localized chromophobe renal cell carcinoma (chRCC). MATERIALS AND METHODS: Clinical data of 36 patients who underwent laparoscopic SE of localized chRCC at our institute were retrospectively analyzed. All patients underwent preoperative renal protocol CT (unenhanced, arterial, venous, and delayed images). CT scan characteristics were evaluated. After intraoperative occlusion of the renal artery, the tumor was free bluntly along the pseudocapsule and enucleated totally. The patients were followed up regularly after the operation. RESULTS: Mean tumor diameter was 3.9±1.0 cm, 80% of tumors were homogeneous and all the tumors had complete pseudocapsule. The attenuation values were slightly lower than normal renal cortex and degree of enhancement of the tumors were significantly lower than normal renal cortex. Mean operation time was 104.3±18.2 min. Mean warm ischemia time (WIT) was 21.3±3.5 min. Mean blood loss was 78.6±25.4 mL. No positive surgical margin was identified. Mean postoperative hospital stay was 5.3±1.5 d. Hematuria occurred in 3 patients and all disappeared within 3 days. After a mean follow-up of 32.1±20.6 months, no patient had local recurrence or metastatic progression. CONCLUSION: Localized chRCCs have a great propensity for homogeneity and complete pseudocapsule. The attenuation values were slightly lower than normal renal cortex and small degree of enhancement. Laparoscopic SE is a safe and effective treatment for localized chRCC. The oncological results were satisfactory.

CLASP2 is involved in the EMT and early progression after transurethral resection of the bladder tumor.

BACKGROUND: Cytoplasmic linker-associated protein 2 (CLASP2) belongs to a family of microtubule plus-end tracking proteins that localizes to the distal ends of microtubules and regulate microtubule dynamics. We speculated that it might be involved in the epithelial-mesenchymal transition (EMT) and progression of bladder cancer (BC). METHODS: Western blotting and RT-PCR were used to detect the changes at protein and mRNA levels in BC cell lines. Cell proliferation, clonogenic formation, wound healing and chamber invasion assay were used to investigate the abilities of cellular proliferation, migration and invasion. The data of BC patients treated with transurethral resection of the bladder tumor (TURBT) was collected and analyzed. The levels of mRNA of CLASP2 and EMT-related markers in tumor and urine samples were tested by RT-PCR. RESULTS: Expressions of CLASP2 varied in four BC cell lines. Manipulation of CLASP2 expression changed EMT-related markers. CLASP2 could promote proliferation, migration and invasion in BC cell lines. The combination (CLASP2 + E-cadherin mRNA in urine) could better discriminate the patients with or without 2-years progression compared with tumor grade after TURBT. CONCLUSION: CLASP2 is involved in the EMT and progression of bladder urothelial cancer. Simultaneous urine-based detection of CLASP2 and E-cadherin mRNA can efficiently discriminate patients with or without 2-years progression after TURBT.

Prevention of Recurrent Bladder Tumors after Nephroureterectomy for Primary Upper Urinary Tract Urothelial Carcinoma: An Individualized Selection Strategy Based on Patient Risk Stratification Is Needed.

OBJECTIVE: To evaluate the efficacies of different chemotherapy regimens in different risk sub-groups for the prevention of bladder recurrence after radical nephroureterectomy (RNU). MATERIALS AND METHODS: Between 2004 and 2012, we recruited 685 patients who underwent RNU for upper tract urothelial carcinoma at 4 Chinese institutions. We assessed whether the type of intravesical chemotherapy regimen affected the bladder recurrence rate in patients with different risk levels after RNU. RESULTS: For all patients, the bladder recurrence rate was lower with intravesical chemotherapy than without, but no significant differences were found between the 2 intravesical chemotherapy regimens (single dose or relatively long-term therapy). We used multivariate analysis to define the risk factors for bladder recurrence and stratified patients into low-, intermediate-, and high-risk sub-groups accordingly. The bladder recurrence rate in the low-risk patients was not significantly different between patients with or without intravesical chemotherapy. However, in the intermediate-risk and high-risk patients, the rate was greater in patients without intravesical chemotherapy than in patients with. Furthermore, the rate was not significantly different between the 2 intravesical chemotherapy regimens in the intermediate-risk patients, while the efficacy of the relatively long-term regimen in high-risk patients remains unclear. CONCLUSIONS: Our study showed that an individualized strategy based on patient risk stratification is needed.