Bladder Urothelial Carcinoma Patients Research Articles

Genome-Wide Analyses of Prognostic and Therapeutic Alternative Splicing Signatures in Bladder Urothelial Carcinoma.

BackgroundAlternative splicing (AS) is an indispensable post-transcriptional modification applied during the maturation of mRNA, and AS defects have been associated with many cancers. This study was designed to thoroughly analyze AS events in bladder urothelial carcinoma (BLCA) at the genome-wide level.MethodsWe adopted a gap analysis to screen for significant differential AS events (DASEs) associated with BLCA. DASEs with prognostic value for OS and the disease-free interval (DFI) were identified by Cox analysis. In addition, a differential AS network and AS clusters were identified using unsupervised cluster analysis. We examined differences in the sensitivity to chemotherapy and immunotherapy between BLCA patients with high and low overall survival (OS) risk.ResultsAn extensive number of DASEs (296) were found to be clinically relevant in BLCA. A prognosis model was established based prognostic value of OS and DFI. CUGBP elav-like family member 2 (CELF2) was identified as a hub splicing factor for AS networks. We also identified AS clusters associated with OS using unsupervised cluster analysis, and we predicted that the effects of cisplatin and gemcitabine chemotherapy would be different between high- and low-risk groups based on OS prognosis.ConclusionWe completed a comprehensive analysis of AS events in BLCA at the genome-wide level. The present findings revealed that DASEs and splicing factors tended to impact BLCA patient survival and sensitivity to chemotherapy drugs, which may provide novel prospects for BLCA therapies.

Promoter hypomethylation as potential confounder of Ras gene overexpression and their clinical significance in subsets of urothelial carcinoma of bladder.

Overexpression of normal Ras and its aberrant CpG island methylation in the promoter regions have been shown to direct cells for uncontrolled abnormal growth and bladder tumor formation and therefore, fetched recent attention as a marker of diagnosis and prognosis to predict the biological behavior of urothelial carcinoma of bladder (UCB). Methylation pattern at CpG islands of the promoter regions of rat sarcoma (Ras) gene homologues namely Kristen-Ras (K-Ras), Harvey (H-Ras), and Neuroblastoma (N-Ras) were examined by methylation specific polymerase chain reaction (MSP). Real time-quantitative polymerase chain reaction (RT-qPCR) was done to determine transcriptomic expressions of these Ras isoforms in the prospective series of 42 NMIBC (non-muscle invasive bladder cancer) and 45 MIBC (muscle invasive bladder cancer) biopsies. CpG loci in H-Ras and K-Ras were observed to be more hypomethylated in MIBC, whereas more hypomethylation in N-Ras was noted in NMIBC. Strong association of hypomethylation index with tumor stage, grade, type and size validate them it as marker of diagnosis in UCB patients. Differential overexpression of H-Ras, N-Ras and K-Ras genes in NMIBC and MIBC and their association with patients' demographics identify them as important diagnostic markers in pathogenesis of UCB. Given the reported ability of promoter hypomethylation to activate Ras expression, correlation studies examined positive significant association between hypomethylation index and expression. Study concludes that promoter hypomethylation of N-Ras and K-Ras could be a potential confounder of their increased expression in NMIBC. Biological significance of simultaneous presence of higher expression and promoter hypomethylation of Ras gene isoforms in MIBC is difficult to resolve in a given cohort of patients.

Identification of a ten-long noncoding RNA signature for predicting the survival and immune status of patients with bladder urothelial carcinoma based on the GEO database: a superior machine learning model.

Bladder urothelial carcinoma (BLCA) is recognized to be immunogenic and tumorigenic. This study identified a novel long noncoding RNA (lncRNA) signature for predicting survival for patients with BLCA. A univariate Cox regression model and the random survival forest-variable hunting (RSF-VH) algorithm were employed to achieve variable selection. Ten lncRNAs (LOC105375787, CYTOR, URB1-AS1, C21orf91-OT1, CASC15, LOC101928433, FLJ45139, LINC00960, HOTAIR and TTTY19) with the highest prognostic values were identified to establish the prognostic model. The nomogram integrating the signature and clinical factors showed high concordance index values of 0.94, 0.7 and 0.90 in the three datasets, and the calibration curves showed concordance between the predicted and observed 3- and 5-year survival rates. The risk score based on the 10-lncRNA signature accurately distinguished high- and low-risk BLCA patients with different disease-specific survival(DSS) or overall survival(OS) outcomes, which were stratified according to clinical factors, including T stage and tumour grade. Gene set enrichment analysis identified BLCA-specific biological pathways and enriched functional categories, such as the cell cycle, DNA repair and immune system. Furthermore, the increased infiltration of immune cells in the high-risk group indicated that lncRNA-related inflammation may reduce the survival of BLCA patients.

MAFG-AS1/MAFG positive feedback loop contributes to cisplatin resistance in bladder urothelial carcinoma through antagonistic ferroptosis

Though promoting ferroptosis can reduce cisplatin resistance in tumor cells, ferroptosis and cisplatin resistance in bladder urothelial carcinoma (BUC) following long non-coding RNAs (lncRNAs) is largely unknown. Here, we found the highly expressed lncRNA MAF transcription factor G antisense RNA 1 (MAFG-AS1) in BUC, and its inhibition increased the sensitivity of BUC cells to cisplatin by promoting ferroptosis. Mechanically, binding to iron chaperone poly(rC)-binding protein 2 (PCBP2) facilitated the recruitments of MAFG-AS1 to deubiquitinase ubiquitin carboxyl-terminal hydrolase isozyme L5 (UCHL5), thus stabilizing PCBP2 protein itself. Then PCBP2 was confirmed to interact with ferroportin 1 (FPN1), an iron export protein, leading to inhibition of ferroptosis. Moreover, the expression of MAFG-AS1 was regulated by the transcriptional factor MAFG. Interestingly, MAFG-AS1 stimulated MAFG transcription by recruiting histone acetyltransferase p300 (EP300) to promote the histone 3 at lysine 27 (H3K27ac) at genomic locus of MAFG, forming a MAFG-AS1/MAFG positive feedback loop. In patient samples, higher expression of MAFG-AS1 and MAFG in BUC tissues was significantly correlated with T status and N status, such that MAFG-AS1, MAFG, and the combination of the two were independent prognostic indicators and chemotherapy sensitivity predictive biomarkers for BUC patients. These findings suggest that inhibition of MAFG-AS1 and MAFG can increase the sensitivity of BUC cells to cisplatin through promoting ferroptosis, indicating the novel chemotherapy sensitivity biomarkers and therapeutic target for BUC.

Prognostic and immunological role of Fam20C in pan-cancer

Background: The family with sequence similarity 20-member C (Fam20C) kinase plays important roles in physiopathological process and is responsible for majority of the secreted phosphoproteome, including substrates associated with tumor cell migration. However, it remains unclear whether Fam20C plays a role in cancers. Here, we aimed to analyze the expression and prognostic value of Fam20C in pan-cancer and to gain insights into the association between Fam20C and immune infiltration.Methods: We analyzed Fam20C expression patterns and the associations between Fam20C expression levels and prognosis in pan-cancer via the ONCOMINE, TIMER (Tumor Immune Estimation Resource), PrognoScan, GEPIA (Gene Expression Profiling Interactive Analysis), and Kaplan–Meier Plotter databases. After that, GEPIA and TIMER databases were applied to investigate the relations between Fam20C expression and immune infiltration across different cancer types, especially BLCA (bladder urothelial carcinoma), LGG (brain lower grade glioma), and STAD (stomach adenocarcinoma).Results: Compared with adjacent normal tissues, Fam20C was widely expressed across many cancers. In general, Fam20C showed a detrimental role in pan-cancer, it was positively associated with poor survival of BLCA, LGG, and STAD patients. Specifically, based on TCGA (The Cancer Genome Atlas) database, a high expression level of Fam20C was associated with worse prognostic value in stages T2–T4 and stages N0–N2 in the cohort of STAD patients. Moreover, Fam20C expression had positive associations with immune infiltration, including CD4+ T cells, macrophages, neutrophils, and dendritic cells, and other diverse immune cells in BLCA, LGG, and STAD.Conclusion: Fam20C may serve as a promising prognostic biomarker in pan-cancer and has positive associations with immune infiltrates.

The Prognostic Significance of Proteasome 26S Subunit, Non-ATPase (PSMD) Genes for Bladder Urothelial Carcinoma Patients.

Proteasome a highly sophisticated systems that alter protein structure and function. Proteasome 26S Subunit, Non-ATPase (PSMD) genes have been implicated in several types of malignancies. This is the first study to look at how proteasomal subunits are expressed in patients with bladder urothelial carcinoma (BLCA). BLCA was used to evaluate the predictive value of PSMD genes (PSMD1 to PSMD12) in relation to clinicopathological characteristics. PSMD genes’ expression patterns at the mRNA level were analyzed using a variety of bioinformatics methods, including gene expression profile integrative analysis (GEPIA), Oncomine, TCGA, and Gene expression Omnibus (GEO) databases. The GEPIA and TCGA dataset survival plot functions were used to assess the prognostic significance of PSMD genes. PSMD2, PSMD3, PSMD4, PSMD8, and PSMD11 genes were significantly overexpressed in BLCA compared with normal bladder tissues. PSMD2 and PSMD8 were significantly overexpressed in BLCA more than other types of cancer. High level of PSMD2 and PSMD8 predicted shorter overall (OS) and progression free survival (PFS) in BLCA patients. High level of PSMD2 was significantly associated with elder age (P < .001), female gender (P = .014), tumor grade (P < .001), and metastasis (P = .003). PSMD2 has been shown to be an independent predictor for OS in BLCA patients based on univariate and multivariate analysis (P < .001). Overall, according to this study, PSMD2 and PSMD8 could be served as a prognostic biomarker for BLCA patients.

Regulatory region mutations of TERT, PLEKHS1 and GPR126 genes as urinary biomarkers in upper tract urothelial carcinomas.

Background: The hotspot regulatory region mutations of the TERT, PLEKHS1 and GPR126 genes have been shown to occur frequently in urothelial bladder carcinoma (UBC). However, it is currently unclear whether these mutations are all present in upper tract urothelial carcinomas (UTUC) including renal pelvic carcinoma (RPC) and ureter carcinoma (UC), although TERT promoter mutations were previously observed in these malignancies.Methods: The hotspot mutations of TERT and PLEKHS1 promoters and GPR126 intron 6 (enhancer) in tumors derived from 164 patients with UTUC were determined using Sanger sequencing, and the obtained results were further compared with the mutation frequency in 106 UBCs. The mutations were also assessed in urine from patients with UTUC and UBC.Results: The mutation frequencies in UTUC tumors were 28%, 5.8% and 11% for TERT and PLEKHS1 promoters and GPR126 intron 6, respectively, which were lower than those (44.3%, 26.4%, and 31.4%, respectively) in UBCs. The total frequencies for the presence of any of these mutations were 50.8% and 34.4% for RPCs and UCs, respectively. All these mutated DNA sequences were detectable in urine from both UTUC and UBC patients and disappeared rapidly in most patients after surgery.Conclusions: This proof-of-concept study demonstrates that the hotspot mutations in the TERT, PLEKHS1 and GPR126 non-coding regions are present in UTUCs, and that urinary assays of these mutated sequences serve as potential biomarkers for UTUC diagnostics and disease monitoring.

Development and validation of a prognostic nomogram for predicting cancer-specific survival after radical cystectomy in patients with bladder cancer:A population-based study.

PurposeTo establish a prognostic model to estimate the cancer‐specific survival (CSS) for urothelial carcinoma of bladder (UCB) patients after radical cystectomy (RC).MethodsA total of 8650 candidates (2004–2011) obtained from the Surveillance, Epidemiology, and End Results (SEER) database were randomly split into development cohort (n = 4323) and validation cohort (n = 4327). We performed Cox regression analysis to identify prognostic factors and Kaplan‐Meier analysis to assess survival outcome. A nomogram predicting CSS was constructed. Its performance was validated by calibration curves, the receiver operating characteristic (ROC) curves, concordance index (C‐index), decision curve analysis (DCA), the net reclassification improvement (NRI), and the integrated discrimination improvement (IDI).ResultsThe nomogram incorporated marital status, T stage, N stage, tumor size, and chemotherapy. In validation cohort, C‐index of the nomogram was 0.707. AUC of the nomogram and AJCC stage were 0.767 versus 0.674. Calibration plots for 3‐ and 5‐year CSS displayed good concordance. DCA curves of the nomogram exhibited larger benefits than the AJCC stage. The NRI and IDI indicated the nomogram outperformed AJCC stage.ConclusionsWe have established a prognostic nomogram with improved discriminative ability and clinical benefits for UCB patients after RC. The nomogram alongside an easy access web tool may assist clinicians in optimizing the postoperative management.

An autophagy-related long non-coding RNA prognostic signature accurately predicts survival outcomes in bladder urothelial carcinoma patients.

In this study, we analyzed the prediction accuracy of an autophagy-related long non-coding RNA (lncRNA) prognostic signature using bladder urothelial carcinoma (BLCA) patient data from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate Cox regression analyses showed significant correlations between five autophagy-related lncRNAs, LINC02178, AC108449.2, Z83843.1, FAM13A-AS1 and USP30−AS1, and overall survival (OS) among BCLA patients. The risk scores based on the autophagy-related lncRNA prognostic signature accurately distinguished high- and low-risk BCLA patients that were stratified according to age; gender; grade; and AJCC, T, and N stages. The autophagy-related lncRNA signature was an independent prognostic predictor with an AUC value of 0.710. The clinical nomogram with the autophagy-related lncRNA prognostic signature showed a high concordance index of 0.73 and accurately predicted 1-, 3-, and 5-year survival times among BCLA patients in the high- and low-risk groups. The lncRNA-mRNA co-expression network contained 77 lncRNA-mRNA links among 5 lncRNAs and 49 related mRNAs. Gene set enrichment analysis showed that cancer- and autophagy-related pathways were significantly enriched in the high-risk group, and immunoregulatory pathways were enriched in the low-risk group. These findings demonstrate that an autophagy-related lncRNA signature accurately predicts the prognosis of BCLA patients.

Construction of Protein-related Risk Score Model in Bladder Urothelial Carcinoma.

Background Though there are several prognostic models, there is no protein-related prognostic model. The aim of this study is to identify possible prognostic-related proteins in bladder urothelial carcinoma and to try to predict the prognosis of bladder urothelial carcinoma based on these proteins. Methods Profile data and corresponding clinical traits were obtained from The Cancer Proteome Atlas (TCPA) and The Cancer Genome Atlas (TCGA) expression. Survival-associated protein in bladder urothelial carcinoma patients were estimated with Kaplan-Meier (KM) test and COX regression analysis. The potential molecular mechanisms and properties of these bladder urothelial carcinoma-specific proteins were also explored with the help of computational skills. The risk score model was validated in different clinical traits. Sankey diagram representation is for protein correlation. A new prognostic-related risk model based on proteins was developed by using multivariable COX analysis. Next, the alteration of the corresponding genes to the 6 prognostic-related proteins was analyzed. Finally, the relation between the corresponding genes and the immune infiltration was analyzed using the TIMER. Results Six proteins were identified to be associated with the prognosis of bladder urothelial carcinoma. A prognostic signature based on proteins (BECLIN, EGFR, PKCALPHA, SRC, ANNEXIN1, and AXL) performed moderately in prognostic predictions. The alteration of corresponding genes was in 31(24%) sequenced cases. ANXA1, AXL, and EGFR were positively related to CD8+ T cell. Conclusion Our results screened six proteins of clinical significance. The importance of a personalized protein signature model in the recognition, surveillance. The abnormal expression of six prognostic-related proteins may be caused by corresponding gene alteration. Furthermore, these proteins may affect survival via the immune infiltration.

Abstract C010: The wiring between genes and short noncoding RNAs in cancer depends on race/ethnicity and sex

Abstract Short noncoding RNAs (ncRNAs) have been attracting increasing interest as regulators of messenger RNA (mRNA) abundance. Such regulatory molecules can have influence the abundance of mRNAs both positively and negatively. Two important categories of short ncRNAs are microRNAs (miRNAs) and their isoforms (isomiRs), and the tRNA-derived fragments (tRFs). We previously showed that their “wiring” with mRNA abundance strongly depends on the race/ethnicity in triple-negative breast cancer. Here, we focused on two cancers, bladder urothelial carcinoma (BLCA) and stomach adenocarcinoma (STAD). Men and women have been known to exhibit different incidence rates of BLCA, as well as differences in invasion, and overall aggressiveness. Analogous observations hold true when comparing White and Asian individuals in the case of STAD. We mined a total of 615 primary tumors, 337 from STAD and 278 from BLCA patients. After stringent abundance filtering, we identified 1,478 distinct isomiRs and 355 distinct tRFs. We found that the abundance profiles of these molecules exhibited strong tissue dependencies. We constructed gene co-expression networks for the healthy and disease states. Mining the correlations of isomiRs/tRFs with mRNAs, we found that core cancer pathways are wired with small ncRNAs. We carried out a large-scale computational analysis of the correlation patterns to dissect the dependencies on race/ethnicity and sex in STAD and BLCA, respectively. We found that core pathways are differentially wired in each case. For example, in BLCA, cell cycle genes are linked with several tRFs in one sex but not in the other. While the contribution of isomiRs in sex disparities in BLCA is limited, we find that isomiRs exhibit strong sex-independent associations with immune system responses and extracellular matrix and cell adhesion. In the case of STAD, we observed several instances of differential-by-race/ethnicity correlations of tRFs with genes involved in cell signaling, like ITPA and PICK1 and numerous cell adhesion genes differentially wired with isomiRs. Our data provide a detailed perspective of the structure and hubs of the gene expression networks in BLCA and STAD as well as their sex- and race/ethnicity-specific components. The identification and discovery of context-specific potential regulators have considerable ramifications for precision medicine and can be leveraged to facilitate the design of better-targeted treatments that are tuned to the patient's sex and race. Citation Format: Aristeidis G. Telonis, Isidore Rigoutsos. The wiring between genes and short noncoding RNAs in cancer depends on race/ethnicity and sex [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C010.

RETRACTED ARTICLE: Acetyl-CoA synthetase 3 promotes bladder cancer cell growth under metabolic stress

Cancer cells adapt to nutrient-deprived tumor microenvironment during progression via regulating the level and function of metabolic enzymes. Acetyl-coenzyme A (AcCoA) is a key metabolic intermediate that is crucial for cancer cell metabolism, especially under metabolic stress. It is of special significance to decipher the role acetyl-CoA synthetase short chain family (ACSS) in cancer cells confronting metabolic stress. Here we analyzed the generation of lipogenic AcCoA in bladder cancer cells under metabolic stress and found that in bladder urothelial carcinoma (BLCA) cells, the proportion of lipogenic AcCoA generated from glucose were largely reduced under metabolic stress. Our results revealed that ACSS3 was responsible for lipogenic AcCoA synthesis in BLCA cells under metabolic stress. Interestingly, we found that ACSS3 was required for acetate utilization and histone acetylation. Moreover, our data illustrated that ACSS3 promoted BLCA cell growth. In addition, through analyzing clinical samples, we found that both mRNA and protein levels of ACSS3 were dramatically upregulated in BLCA samples in comparison with adjacent controls and BLCA patients with lower ACSS3 expression were entitled with longer overall survival. Our data revealed an oncogenic role of ACSS3 via regulating AcCoA generation in BLCA and provided a promising target in metabolic pathway for BLCA treatment.

Slingshot homolog-1 expression is a poor prognostic factor of pT1 bladder urothelial carcinoma after transurethral resection

ObjectiveSlingshot homolog-1 (SSH-1) shows an important role in the occurrence and development in various tumors. While, the expression and prognostic implications of SSH-1 in bladder urothelial carcinoma (UC) remain unclear and thus were addressed in this study.MethodsImmunohistochemistry (IHC) was performed on tissue microarrays composed of 624 bladder UC specimens after transurethral resection of bladder tumor (TUR-BT) to detect SSH-1 expression. The clinic-pathological features were compared between SSH-1( +) and SSH-1(−) subgroups. The Kaplan–Meier curve with log-rank test and univariate/multivariate Cox regression model with stepwise backward elimination methods were performed for survival analyses.ResultsIn this study, 359 (57.53%) specimens were detected with SSH-1 expression. SSH-1 positivity was significantly associated with higher pathological grade (p = 0.020), lymphovascular invasion (p = 0.006), tumor recurrence (p < 0.001) and progression (p < 0.001) in bladder UC. Besides, SSH-1 positivity predicted a shorter overall survival (OS, p = 0.024), recurrence-free survival (RFS, p < 0.001), progression-free survival (PFS, p = 0.002) and cancer-specific survival (CSS, p = 0.047). Multivariate Cox proportional hazard analysis showed that tumor size (p = 0.007), lymphovascular invasion (p = 0.003), recurrence (p < 0.001), progression (p < 0.001) and SSH-1 expression (p = 0.015) were predictors of poor prognosis in bladder UC patients.ConclusionsSSH-1 expression was associated with undesirable clinic-pathological characteristics and poor post-operative prognosis in bladder UC patients. SSH-1 might play an important role in bladder UC and serve as a promising predictor of oncological outcomes in patients with bladder UC.

Fibroblasts in urothelial bladder cancer define stroma phenotypes that are associated with clinical outcome

Little attention was given to the interaction between tumor and stromal cells in urothelial bladder carcinoma (UBC). While recent studies point towards the existence of different fibroblast subsets, no comprehensive analyses linking different fibroblast markers to UBC patient survival have been performed so far. Through immunohistochemical analysis of five selected fibroblast markers, namely alpha smooth muscle actin (ASMA), CD90/Thy-1, fibroblast activation protein (FAP), platelet derived growth factor receptor-alpha and -beta (PDGFRa,-b), this study investigates their association with survival and histopathological characteristics in a cohort of 344 UBC patients, involving both, muscle-invasive and non-muscle-invasive cases. The data indicates that combinations of stromal markers are more suited to identify prognostic patient subgroups than single marker analysis. Refined stroma-marker-based patient stratification was achieved through cluster analysis and identified a FAP-dominant patient cluster as independent marker for shorter 5-year-survival (HR(95% CI)2.25(1.08–4.67), p = 0.030). Analyses of interactions between fibroblast and CD8a-status identified a potential minority of cases with CD90-defined stroma and high CD8a infiltration showing a good prognosis of more than 80% 5-year-survival. Presented analyses point towards the existence of different stroma-cell subgroups with distinct tumor-modulatory properties and motivate further studies aiming to better understand the molecular tumor–stroma crosstalk in UBC.

Bioinformatic Identification of Potential Hub Genes in Muscle-Invasive Bladder Urothelial Carcinoma

Despite aggressive treatment approaches, muscle-invasive bladder urothelial carcinoma (MIBC) patients still have a 50% chance of developing general incurable metastases. Therefore, there is an urgent need for candidate markers to enhance diagnosis and generate effective treatments for this disease. We evaluated four mRNA microarray datasets to find differences between non-MIBC (NMIBC) and MIBC tissues. Through a gene expression profile analysis via the Gene Expression Omnibus database, we identified 56 differentially expressed genes (DEGs). Enrichment analysis of gene ontology, Kyoto Encyclopedia of Genes and Genomes, and Reactome pathways revealed the interactions between these DEGs. Next, we established a protein-protein interaction network to determine the interrelationship between the DEGs and selected 10 hub genes accordingly. Bladder urothelial carcinoma (BLCA) patients with COL1A2, COL5A1, and COL5A2 alterations showed poor disease-free survival rates, while BLCA patients with COL1A1 and LUM alterations showed poor overall survival rates. Oncomine analysis of MIBC versus NMIBC tissues showed that COL1A1, COL5A2, COL1A2, and COL3A1 were consistently among the top 20 overexpressed genes in different studies. Using the TCGAportal, we noted that the high expression of each of the four genes led to shorter BLCA patient overall survival. It was evident that BLCA patients with an elevated high combined gene expression had significantly shorter overall survival and relapse-free survival than those with low combined gene expression using PROGgeneV2. Using Gene Expression Profiling Interactive Analysis, we noted that COL1A1, COL1A2, COL3A1, and COL5A2 were positively correlated with each other in BLCA. These genes are considered as clinically relevant genes, suggesting that they may play an important role in the carcinogenesis, development, invasion, and metastasis of MIBC. However, considering we adopted a bioinformatic approach, more research is crucial to confirm our results. Nonetheless, our findings may have important prospective clinical implementations.

Enhanced CDR1as Promotes the Development of Bladder Urothelial Carcinoma.

The current study aimed to evaluate the expression of circular RNA (circRNA) CDR1as in bladder urothelial carcinoma and adjacent normal tissues, thereby laying the foundation for the research of bladder urothelial carcinoma. The level of CDR1as was evaluated in the tissues of bladder urothelial carcinoma patients. ROC analysis was carried out to explore the possible diagnostic value of CDR1as. In the current study, we showed novel data that the expression of CDR1as in bladder urothelial carcinoma tissues was significantly higher than that in adjacent tissues. Furthermore, the expression of CDR1as was significantly higher in non-muscle invasive bladder cancer (NMIBC) and high-grade cancer tissues than in muscle invasive bladder cancer (MIBC) and low-grade cancer tissues. In patients with lymph node metastasis, the expres-sion of CDR1as was also significantly higher. Moreover, the expression of CDR1as was higher in high-stage, high-grade bladder urothelial carcinoma than in low-stage and low-grade cancer tissues. Real time PCR analysis showed that there was no difference in the expression of CDR1as among the patients according to the grouping of gender (male vs. female), age (≤ 65 years vs. > 65 years), tumor size (≤ 3 cm vs. > 3 cm), and lymphatic invasion (LVI). The current study for the first time showed upregulation of CDR1as may be involved in the development and progression of bladder urothelial carcinoma.

A radiogenomics signature for predicting the clinical outcome of bladder urothelial carcinoma.

To determine the integrative value of contrast-enhanced computed tomography (CECT), transcriptomics data and clinicopathological data for predicting the survival of bladder urothelial carcinoma (BLCA) patients. RNA sequencing data, radiomics features and clinical parameters of 62 BLCA patients were included in the study. Then, prognostic signatures based on radiomics features and gene expression profile were constructed by using least absolute shrinkage and selection operator (LASSO) Cox analysis. A multi-omics nomogram was developed by integrating radiomics, transcriptomics and clinicopathological data. More importantly, radiomics risk score-related genes were identified via weighted correlation network analysis and submitted to functional enrichment analysis. The radiomics and transcriptomics signatures significantly stratified BLCA patients into high- and low-risk groups in terms of the progression-free interval (PFI). The two risk models remained independent prognostic factors in multivariate analyses after adjusting for clinical parameters. A nomogram was developed and showed an excellent predictive ability for the PFI in BLCA patients. Functional enrichment analysis suggested that the radiomics signature we developed could reflectthe angiogenesis status of BLCA patients. The integrative nomogram incorporated CECT radiomics, transcriptomics and clinical features improved the PFI prediction in BLCA patients and is a feasible and practical reference for oncological precision medicine. • Our radiomics and transcriptomics models are proved robust for survival prediction in bladder urothelial carcinoma patients. • A multi-omics nomogram model which integrates radiomics, transcriptomics and clinical features for prediction of progression-free interval in bladder urothelial carcinoma is established. • Molecular functional enrichment analysis is used to reveal the potential molecular function of radiomics signature.

Development of a novel six-long noncoding RNA signature predicting survival of patients with bladder urothelial carcinoma.

Bladder urothelial carcinoma is a malignant tumor with a high incidence in the uropoietic system. Considerable studies have shown that long noncoding RNA (lncRNA) plays an important role in the development and progression of bladder urothelial carcinoma. In this study, the lncRNA expression and clinical data of 377 bladder urothelial carcinoma patients were obtained from The Cancer Genome Atlas database and differentially expressed lncRNAs in cancer and normal groups were evaluated. Univariate COX and multivariate COX regression analyses of prognosis were performed on differentially expressed lncRNAs in the training data sets, six prognosis-related lncRNAs (LINC02195, LINC01484, LINC01468, SMC2-AS1, AC011298.1, and PTPRD-AS1) were assessed, and a six-lncRNA signature was constructed. The predictive capability of this six-lncRNA signature was validated in the testing data sets and entire data sets. The prognostic ability of the six-lncRNA signature was independent of other clinical elements after multivariate COX regression and stratified analyses of with other clinical elements. We performed functional enrichment analysis with the six prognosis-related lncRNAs. Results of functional enrichment revealed that these prognosis-related lncRNAs might promote the development and metastasis of bladder urothelial carcinoma. In summary, the six-lncRNA signature that we developed could effectively predict the prognosis of bladder urothelial carcinoma patients. This six-lncRNA signature might be a novel independent prognostic marker of bladder urothelial carcinoma. Moreover, it also provides novel insights into the mechanism of bladder urothelial carcinoma.

Immune Checkpoint Human Endogenous Retrovirus-H Long Terminal Repeat-Associating Protein 2 is Upregulated and Independently Predicts Unfavorable Prognosis in Bladder Urothelial Carcinoma

Background/Aims: human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) is highly expressed in multiple solid malignant tumors, making it a potential biomarker for tumorigenesis and invasion. However, the expression and clinical significance of HHLA2 in bladder urothelial carcinoma (BUC) have not been extensively studied. This study aimed to investigate the relationship between HHLA2 expression and clinicopathological characteristics of BUC. Methods: A total of 212 patients pathologically diagnosed with BUC were included in this study. HHLA2 expression was analyzed by immunohistochemical staining and qRT-polymerase chain reaction. Correlations of HHLA2 expression and pathological characteristics, including 5-year recurrence-free survival (RFS) and overall survival (OS) were examined, and the diagnostic value of HHLA2 was estimated by using the receiver operating characteristic (ROC) curve. Results: Immunohistochemical staining showed that the expression of HHLA2 was significantly upregulated in BUC tissues compared with normal bladder tissues. In BUC tissues, HHLA2 expression was significantly associated with tumor size, tumor stage, tumor grade, and lymph node metastasis (all p < 0.05). HHLA2 expression was an independent prognostic factor of tumor metastasis (p < 0.05). The Kaplan-Meier survival curve revealed that high HHLA2 expression was significantly correlated with the poor RFS and OS of BUC patients (both p < 0.05), and the ROC curve showed HHLA2 could be a good diagnostic marker. Conclusions: HHLA2 can independently predict unfavorable prognosis in BUC.

MicroRNA-101-3p advances cisplatin sensitivity in bladder urothelial carcinoma through targeted silencing EZH2.

Objective: Chemotherapy is a major therapeutic method for bladder urothelial carcinoma (BUC), which can effectively improve the prognosis of BUC patients, but the chemoresistance often leads to chemotherapy failure. This study will research the regulatory roles and molecular mechanism of miR-101-3p in BUC chemoresistance.Materials and Methods: The quantitative real-time PCR was used to detect the expression of miRNA-101-3p and EZH2. The proliferation and chemoresistance were analyzed by CCK8 assay. Luciferase reporter assay was used to verify the combination between miR-101-3p and EZH2. Protein expression was detected by Western blotting. Flow cytometry was used to examine apoptosis rate.Results: The miR-101-3p expression was down-regulated in cisplatin (CDDP) resistant BUC cell line (T24/CDDP) and tissues, and was positively related to sensitivity of BUC to CDDP. In T24/CDDP cells, the up-regulation of miR-101-3p decreased the half maximal inhibitory concentration (IC50) to CDDP, depressed the expression of MRP1 protein, promote the CDDP-induced cytotoxicity, and advanced CDDP sensitivity. A series of in vitro experiments certified the EZH2 gene was a target gene of miR-101-3p, including luciferase reporter assay, western blotting and so on. Up-regulation of EZH2 largely reversed the regulatory effects of miR-101-3p enhancement on CDDP sensitivity in T24/CDDP cells.Conclusion: The expression of miR-101-3p is positively related to CDDP sensitivity of BUC, miR-101-3p advances sensitivity of BUC to CDDP through targeted silencing EZH2.