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Bladder cancer (BC) is one of the most prevalent malignancies worldwide, but it lacks effective targeted therapy due to its elusive molecular mechanism. Therefore, it is important to further investigate the molecular mechanisms that mediate BC progression. By performing a tumor tissue-based gene microarray and shRNA library screening, we found that recombination signal binding protein for immunoglobulin kappa J region (RBPJ) interacting and tubulin associated 1 (RITA1) is crucial for the growth of BC cells. Moreover, RITA1 is aberrantly highly expressed in BC tissues and is also correlated with poor prognosis in patients with BC. Mechanistically, we determined that RITA1 recruits tripartite motif containing 25 (TRIM25) to ubiquitinate RBPJ to accelerate its degradation via proteasome, which leads to the transcriptional inhibition of Notch1 downstream targets. Our results suggest that aberrant high expression of RITA1 drives the growth of BC cells via the RITA1/TRIM25/RBPJ axis and RITA1 may serve as a promising therapeutic target for BC.

Transcription dysregulation is a salient characteristic of bladder cancer (BC), but no appropriate therapeutic target for it has been established. Here, we found that heterogeneous downregulation of histone H4 transcription factor (HINFP) was associated with senescence in BC tissues and that lower HINFP expression could predict an unfavorable outcome in BC patients. Knockout of HINFP transcriptionally inhibited H1F0 and H1FX to trigger DNA damage, consequently inducing cell senescence to repress the proliferation and growth of BC cells. However, the senescence-associated secretory phenotype, characterized by increases in MMP1/3, enhances the invasion and metastasis of non-senescent BC cells. Histone deacetylase inhibitors (HDACis) could efficiently eliminate the senescent cells induced by HINFP knockout to suppress the invasion and metastasis of BC cells. Our study suggests that HDACis, widely used in multiple cancer types in a clinical context, may also benefit BC patients with metastases induced by cell senescence.

Introduction Unlike the established evidence to use chemotherapy for urothelial carcinoma of the bladder, presently there are insufficient data to inform a recommendation on upper urinary tract urothelial carcinoma treatment. The prognosis for patients with stage T4 and positive lymph nodes is poor; however, primary tumors in the renal pelvis are associated with favorable prognoses compared to those located in the ureter. Our study aimed at investigating the effectiveness of chemotherapy in patients with pT3N0M0 renal pelvic urothelial carcinomas (RPUC) who have relative favorable prognosis. Methods Patients with pT3N0M0 tumors who underwent radical nephroureterectomy combined with bladder cuff excision between 2005 and 2014 and registered in the Surveillance, Epidemiology, and End Results database were eligible for inclusion (n = 939). Baseline characteristics between the chemotherapy and observation groups were controlled for with inverse probability of treatment weighting (IPTW)‐adjusted analysis. Results After the IPTW‐adjusted analysis, the 5‐year IPTW‐adjusted rates of overall survival (OS) for the chemotherapy and observation groups were 53.1% and 44.9%, respectively. The IPTW‐adjusted Kaplan‐Meier curves suggested that chemotherapy was associated with increased OS compared with observation (P = .028). In the IPTW‐adjusted Cox proportional hazards regression model, chemotherapy was associated with favorable survival benefits compared with observation (hazard ratio [HR] 0.71, 95% CI 0.52‐0.92, P = .031), and this was maintained after bootstrapping (HR 0.72, 95% CI 0.49‐0.93). Chemotherapy had a protective effect on OS benefits, which were found in a majority of the results of the subgroup analysis and were consistent with the main results (all P‐interactions > 0.05). Conclusion Chemotherapy may provide significant OS benefits for patients with pT3N0M0 RPUC. The results of our study could strengthen the evidence for using adjuvant chemotherapy in this rare group of patients., Chemotherapy appears to provide significant overall survival benefits for patients with pT3N0M0 renal pelvic urothelial carcinomas. Our results showed that the effectiveness of chemotherapy is not related to the tumor size and pattern of invasion. The findings of our study could strengthen the evidence for using adjuvant chemotherapy for this rare group of patients.

Purpose To indirectly compare the efficacy and safety of systemic therapies used for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). Methods The relevant randomized controlled trials were retrieved from PubMed and the Cochrane Library. Network meta-analyses were used to compare multiple drugs simultaneously for the outcomes of nmCRPC. Direct evidence in trials and indirect evidence across trials were combined by the network meta-analyses to estimate the treatment efficiency. Outcome Eight studies were included in our research. For prostate-specific antigen progression-free survival, the rate of progression was significantly decreased following apalutamide, enzalutamide, bicalutamide+dutasteride, and bicalutamide treatment compared with placebo. Compared with placebo treatment, metastases-free survival was significantly increased in patients who received apalutamide (hazard ratio [HR]: 0.28, 95% confidence interval [CI]: 0.23-0.35), enzalutamide (HR: 0.29, 95% CI: 0.24-0.35), and darolutamide (HR: 0.42, 95% CI: 0.35-0.50). Direct comparison showed significant survival benefits in patients who received second-generation anti-androgen therapy (apalutamide, enzalutamide, and darolutamide: HR: 0.74, 95% CI: 0.61-0.91) compared with patients who received placebo. With respect to metastases-free survival, based on SUCRA analysis, there was 80% and 78% probability that apalutamide and enzalutamide were preferred treatment, while darolutamide was likely to be second-best choice. Compared with placebo, all agents were not associated with significantly higher likelihood of serious adverse events and grade 3 to 4 adverse events. Conclusion Our outcomes support equivalent efficacy and similar risk of adverse effects between apalutamide, enzalutamide, and darolutamide, supporting the use of these antiandrogen agents in high-risk of progression nmCRPC.

Multidrug resistance gene 1 (MDR1), a key factor contributing to drug insensitivity, has been associated with treatment failure and poor prognoses in various cancers, including bladder urothelial carcinoma (UC). Here we show that positive Nkx2.8 expression was associated with better prognosis of UC patients received chemotherapy. Patients with positive Nkx2.8 expression had promising prognosis from adjuvant chemotherapy. Enforced expression of Nkx2.8 promotes drug sensitivity of UC cells. Mechanistic investigations showed that Nkx2.8 negatively regulated expression of MDR1 by binds directly to the MDR1 promoter and transcriptionally represses MDR1 expression. P-gp inhibitor reversed chemosensitivity inhibition by Nkx2.8 scilencing. In clinical UC specimens, expression of Nkx2.8 inversely correlated with P-gp expression, and UC patients with Nkx2.8 positivity and low P-gp expression displayed the best prognosis. Our findings uncovered a new mechanism of chemosensitivity in UC cells and proposing Nkx2.8-MDR1 axis as a novel candidate target for therapeutic intervention of UC.

Background: A great number of metabolic genes have been discovered in gastric cancer (GC); however, their prognostic roles remain incompletely clear so far. Methods: The Cancer Genome Atlas-stomach adenocarcinoma, and GSE84437 dataset collected via the Gene Expression Omnibus (GEO) database were utilized for retrieving those clinicopathological data and RNA expression patterns. Besides, the signature was obtained through the lasso Cox regression model and univariate Cox regression analysis. A novel 13-gene metabolic signature (including GSTA2, POLD3, GLA, GGT5, DCK, CKMT2, ASAH1, OPLAH, ME1, ACYP1, NNMT, POLR1A, and RDH12) was constructed for predicting the prognosis for gastric adenocarcinoma. Results: The results suggested that, the survival in high risk group was remarkably dismal compared with that in low risk group. In addition, that as-constructed signature had been identified as a factor to independently predict the prognosis for gastric adenocarcinoma patients. Moreover, the signature-based nomogram showed certain benefits in predicting the overall survival (OS). Besides, results of gene set enrichment analysis (GSEA) suggested that some pathways were markedly enriched, which help to illustrate the possible mechanisms. Conclusions: The new 13-gene metabolic model is constructed in this study to predict the prognosis for GC. It probably reflects dysregulation in the metabolic microenvironment, in the meantime of providing metabolic treatment biomarkers, and predicting the treatment response to gastric adenocarcinoma.

Background The survival benefit of partial nephrectomy (PN) in pT3a RCC patients is controversial. Here we aimed to determine the benefit of PN for T3aN0M0 renal cell carcinoma (RCC). Methods Data of patients with pT3aN0M0 RCC who were diagnosed between 2010–2012 in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database were retrospectively collected. We compared overall survival (OS) and cancer specific survival (CSS) using a Cox proportional hazards model between PN and radical nephrectomy (RN) in pT3aN0M0 RCC. Propensity score (–adjusted, –stratified, –weighted, and –matched) analyses were performed to control for imbalances in individual risk factors. Results A total of 1277 patients with pT3aN0M0 RCC were identified, of whom 200 patients were treated with PN and 1077 patients were RN. Patients who received PN were more likely to have small tumor size, well/moderately differentiation, peritumoral fat invasion, and less likely to have multiple site invasion and clear cell adenocarcinoma type (p

Owing to the aggressive nature of radical nephroureterectomy (RNU), it is extremely important for the diagnostic modalities to be accurate. The European Association of Urology guidelines recommend that diagnostic ureteroscopy (URS) and biopsy be performed for upper urinary tract urothelial carcinomas (UUTCs). But that diagnostic URS adversely affects oncologic outcomes still exist. In the current systematic review and meta-analysis, we had attempted to evaluate oncologic outcome of diagnostic URS before RNU.All relevant articles were retrieved from PubMed, Embase, Web of Science, and the Cochrane Library. Endpoint events were recurrence-free survival, metastasis-free survival, cancer-specific survival, and overall survival.Compared with patients who underwent RNU alone, those who underwent diagnostic URS before RNU had significantly higher intravesical recurrence rate (HR = 1.42, 95% CI: 1.24-1.61, IDiagnostic URS before RNU does not seem to compromise long-term survival outcomes, even though it is associated with a higher rate of intravesical recurrence (IVR). Our findings suggest that further investigation, especially through prospective studies, should focus on decreasing the rate of IVR by administration of intravesical chemotherapy immediately after diagnostic URS.

Cystatin-C (Cys-C) has been studied as a valuable prognostic indicator in several malignancies. The goal of this study is to explore the expression and prognostic significance of Cys-C in clear cell renal cell carcinoma (CCRCC).Immunohistochemistry and western blot assays were performed to evaluate the level of Cys-C expression in CCRCC tissue. Expression levels of Cys-C in CCRCC tissue samples in relation to clinicopathological characteristics of the tumors were assessed. Their prognostic significance was analyzed by univariate and multivariate analyses. In addition, the expression of Cys-C in 786-O cell lines was inhibited by using CRISPR/Case9 and the effects of Cys-C knockout on 786-O cells in vitro were evaluated using MTT method, colony formation assay, cell cycle assay, and cell migration and invasive assay.The expression level of Cys-C was lower in CCRCC tissues (n = 253) than in paired adjacent non-cancerous tissues (n = 164) by immunohistochemistry (P 0.001). Among the 253 patients, the results showed that patients with low Cys-C expression level in cancer tissue has longer overall survival (OS) than that with high Cys-C level. Furthermore, knockout of Cys-C in 786-O cell line has ability to suppress cell proliferation, induce G0/G1 phase arrest, inhibited cell invasion, decreased phosphorylation of ERK1/2, STAT-3 and enhanced phosphorylated JNK expression.A decrease in serum Cys-C is a favorable prognostic indicator for CCRCC patients. Inhibition of Cys-C suppressed RCC 786-O cell proliferation and invasion. These results indicated that Cys-C could serve as an ideal prognostic biomarker in patients with CCRCC.

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A vital constituent of the centrosome involved in regulating the activity of the organelle during the cell cycle is centrosomal protein (CEP)-72, whose function in the case of human cancer yet lacks clarity. The expression dynamics of CEP72 and its clinical impact were examined in a large cohort of bladder tissues. Several experiments at both the in vitro and in vivo levels on urothelial carcinoma of the bladder (UCB) cells were conducted to understand the role of this molecule along with the mechanisms. Overexpression of CEP72 in UCB was linked with the acquisition of an aggressive phenotype, which was associated with poor prognosis. In UCB cell lines, knockdown of CEP72 using shRNA was sufficient to inhibit cell invasiveness/metastasis, whereas ectopic overexpression of CEP72 promoted cell invasiveness and/or metastasis both in vitro and in vivo. CEP72 was demonstrated to induce UCB cell aggressiveness via up-regulation of an important target downstream, the serpin family member 1 gene (SERPINE1) (alias plasminogen activator inhibitor, PAI1), ultimately leading to increased cancer cell invasiveness. Particularly, overexpression of CEP72 was associated with a sizable increase in cAMP response element–binding protein binding at the SERPINE1 promoter, leading to increased SERPINE1 transcription. Such observations are suggestive of the potential use of CEP72 as a therapeutic tool for UCB.

To investigate the effects of intra-arterial chemotherapy on T1 stage bladder cancer (Bca) and evaluate patient outcome with bladder-preserving treatment approaches. A total of 238 patients with T1 stage Bca were retrospectively analyzed. Among them, 35 patients were categorized into the subgroup of highest-risk T1 stage according to the European Association of Urology guidelines and received immediate radical cystectomy (RC group), whereas 62 were classified as being highest-risk T1 patients but were unwilling to undergo RC and were treated with gemcitabine plus cisplatin intra-arterial chemotherapy (GC group). There were 141 T1 patients who had bladder-preserving surgery with intravesical chemotherapy (IVC group). For patients with T1 stage Bca, the GC group had a higher estimated recurrence-free survival rate (44.4 vs. 13.9%, P = 0.087), progression-free survival rate (75.4 vs. 32.8%, P = 0.006), and cancer-specific survival (CSS) rate (78.7 vs. 67.5%, P = 0.399) when compared with the IVC group, respectively. Using the multivariable regression model, the GC intra-arterial chemotherapy was significantly related to bladder preservation (P = 0.004), lower recurrence (P = 0.012), and less progression (P = 0.004). For patients with the highest-risk T1 stage, GC group did not have a poorer CSS rate in comparison with the RC group (P = 0.383). Moreover, immediate RC did not confer a survival benefit in terms of CSS when compared with those who underwent deferred RC after failing GC intra-arterial chemotherapy (P = 0.283). Gemcitabine plus cisplatin intra-arterial chemotherapy may be an effective bladder-preserving alternative adjuvant treatment for patients with T1 stage Bca with oncologic benefits, good compliance, and low toxicity.

Background The 7th Tumor-Node-Metastasis system for clear cell renal cell carcinoma (ccRCC) classified renal sinus fat invasion (SFI), perirenal fat invasion (PFI), or renal vein invasion (RVI) as stage pT3a. However, their close interactions and prognostic value of them remain controversial. The goal of this study is to further analyze their prognostic values for patients with T3aN0M0 ccRCC. Methods The data of 1,869 pT3aN0M0 ccRCC patients receiving the radical nephrectomy surgery were collected from the National Cancer Institute Surveillance, Epidemiology, and End Results database of United states from 2010 to 2014. These Patients were grouped as SFI, PFI, SFI + RVI, SFI + PFI, PFI + RVI, and SFI + PFI + RVI according to their corresponding manifestations. Cancer-specific survival (CSS) was determined using the Kaplan–Meier method. Univariate and Multivariate cox proportional-hazards regression methods were used to evaluate the impacts of clinical pathologic parameters on CSS. Results Patients with SFI or PFI alone had the similar CSS (P = 0.286) and patients with SFI + PFI + RVI had the worst outcomes. Moreover, significantly more patients with SFI + PFI + RVI had tumor diameter ≥7cm than patients with PFI + RVI, SFI + PFI (68.80% vs. 65.32%, 58.77%, and 55.04%, P = 0.026), respectively. Multivariable analysis showed that RVI + PFI (P = 0.013) and PFI + SFI + RVI (P = 0.011) were the independent factors of CSS. Conclusions The results suggest that invasion location can help distinguish patients with T3aN0M0 ccRCC with increased risk of cancer-related mortality.