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Objectives: This study aims to reveal immunophenotypes associated with immunotherapy response in bladder cancer, identify the signature genes of immune subtypes, and provide new molecular targets for improving immunotherapy response., Methods: Bladder cancer immunophenotypes were characterized in the bulk RNA sequencing dataset GSE32894 and Imvigor210, and gene expression signatures were established to identify the immunophenotypes. Expression of gene signatures were validated in single-cell RNA sequencing dataset GSE145140 and human proteins expression data source. Investigation of Immunotherapy Response was performed in IMvigor210 dataset. Prognosis of tumor immunophenotypes was further analyzed., Results: Inflamed and immune-excluded immunophenotypes were characterized based on the tumor immune cell scores. Risk score models that were established rely on RNA sequencing profiles and overall survival of bladder cancer cohorts. The inflamed tumors had lower risk scores, and the low-risk tumors were more likely to respond to atezolizumab, receiving complete response/partial response (CR/PR). Patients who responded to atezolizumab had higher SRRM4 and lower NPHS1 and TMEM72 expression than the non-responders. SRRM4 expression was a protective factor for bladder cancer prognosis, while the NPHS1 and TMEM72 showed the opposite pattern., Conclusion: This study provided a novel classification method for tumor immunophenotypes. Bladder cancer immunophenotypes can predict the response to immune checkpoint blockade. The immunophenotypes can be identified by the expression of signature genes., (© 2023 The Japanese Urological Association.)

Background: Bladder cancer (BLCA) is a malignant tumor occurring in bladder mucosa. Metadherin (MTDH) has been implicated in tumor progression; however, its molecular biological mechanisms in BLCA remain unclear. Materials and Methods: Cell functions were tested after BLCA cells were transfected by both short hairpin RNAs and small interfering RNAs to silence MTDH. Furthermore, in-house RNA sequencing (RNA-seq) was performed with T24 cells after the knockdown of MTDH. In addition, MTDH-related pathways were explored. Finally, MTDH mRNA and protein expression levels were examined using multiple detection methods in BLCA tissues. Results: MTDH knockdown could largely inhibit cell proliferation, viability, and migration and induce apoptosis of BLCA cells. In-house RNA-seq showed that MTDH knockdown led to extracellular matrix organization and cell division. The integrated analysis showed that the comprehensive expression of MTDH at the mRNA level was 0.47 and that at the protein level was 0.54, based on 11 platforms, including 1485 BLCA and 180 non-BLCA samples. Conclusions: MTDH promotes the growth of BLCA cells through the pathway of cell division. This study provides new directions and biomarkers for future treatment.

Nitidine chloride (NC) is effective on cancer in many tumors, but its effect on bladder cancer (BC) is unknown. We conducted cell function experiments to verify the antineoplastic effect of NC on BC cell lines (5637, T24, and UM-UC-3) in vitro. Then, mRNAs of NC-treated and NC-untreated BC cells were extracted for mRNA sequencing. Differentially expressed genes (DEGs), expression analysis, and drug molecular docking were conducted to discover the target gene of NC. Finally, functional enrichment was analyzed to explore the underlying mechanisms. NC dramatically inhibited proliferation, migration, and invasion, and it induced apoptosis and arrested the S and G2/M phases of BC cell lines. Lymphocyte antigen 75 (LY75) appeared to be the target of NC. LY75 was highly expressed and had the ability to distinguish BC tissue from non-cancerous tissue. Then, drug molecular docking confirmed the targeting relationship between NC and LY75. Gene enrichment analysis showed that the downregulated genes, after being treated with NC, were mainly enriched in pathways relevant to cell pathophysiological processes. NC inhibits BC cell proliferation, migration, and invasion, induces apoptosis, and arrests cell cycles by downregulating the expression of LY75. This study provides molecular and theoretical bases for NC treatment of BC., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Bladder cancer (BC) is a common cancer worldwide with a high prevalence. This study was conducted to elucidate the expression and clinical significance of Sorbin and SH3 domain-containing protein 1 (SORBS1) in BC as well as to explore its molecular mechanism in BC tumourigenesis. RNA-sequencing data, microarray, and Immunohistochemistry (IHC) were applied to elucidated the SORBS1 expression at multiple levels. After that, the relationship between tumour-immune infiltration and SORBS1 was also explored. Finally, SORBS1-related genes in BC were identified to perform functional enrichment analyses. The expression integration revealed that the comprehensive expression of SORBS1 at the mRNA level was -1.02 and that at the protein level was -3.73, based on 12 platforms, including 1221 BC and 187 non-BC samples. SORBS1 was negatively correlated with tumour purity (correlation = -0.342, p < 0.001) and positively correlated with macrophage (correlation = 0.358, p < 0.001). The results of enrichment analyses revealed that the most significant biological pathways of SORBS1-related genes were epithelial-mesenchymal transition. SORBS1 was significantly down-regulated in BC and may play a role as tumour suppressor. This study provides new directions and biomarkers for future BC diagnosis., (© 2023 The Authors. IET Systems Biology published by John Wiley & Sons Ltd on behalf of The Institution of Engineering and Technology.)

Background: Pituitary tumor transforming gene-1 (PTTG1) transcription factor is identified as carcinogenic and associated with tumor invasiveness, but its role in bladder cancer (BLCA) remains obscure. This research is intended to analyze the aberrant expression and clinical significance of PTTG1 in BLCA, explore the relationship between PTTG1 and tumor microenvironment characteristics and predict its potential transcriptional activity in BLCA tissue., Methods: We compared the expression discrepancy of PTTG1 mRNA in BLCA and normal bladder tissue, using the BLCA transcriptomic datasets from GEO, ArrayExpress, TCGA, and GTEx. In-house immunohistochemical staining was implemented to determine the PTTG1 protein intensity. The prognostic value of PTTG1 was evaluated using the Kaplan-Meier Plotter. CRISPR screen data was utilized to estimate the effect PTTG1 interference has on BLCA cell lines. We predicted the abundance of the immune cells in the BLCA tumor microenvironment using the microenvironment cell populations-counter and ESTIMATE algorithms. Single-cell RNA sequencing data was applied to identify the major cell types in BLCA, and the dynamics of BLCA progression were revealed using pseudotime analysis. PTTG1 target genes were predicted by CistromeDB., Results: The elevated expression level of PTTG1 was confirmed in 1037 BLCA samples compared with 127 non-BLCA samples, with a standardized mean difference value of 1.04. Higher PTTG1 expression status exhibited a poorer BLCA prognosis. Moreover, the PTTG1 Chronos genetic effect scores were negative, indicating that PTTG1 silence may inhibit the proliferation and survival of BLCA cells. With PTTG1 mRNA expression level increasing, higher natural killer, cytotoxic lymphocyte, and monocyte lineage cell infiltration levels were observed. A total of four candidate targets containing CHEK2, OCIAD2, UBE2L3, and ZNF367 were determined ultimately., Conclusions: PTTG1 mRNA over-expression may become a potential biomarker for BLCA prognosis. Additionally, PTTG1 may correlate with the BLCA tumor microenvironment and exert transcriptional activity by targeting CHEK2, OCIAD2, UBE2L3, and ZNF367 in BLCA tissue., (© 2022. The Author(s).)

Bladder cancer (BC) ranks as the ninth most commonly diagnosed cancer worldwide. The presence of a transcription factor (TF) has been uncovered as a significant contributor to the pathophysiological changes of cancers. In present study, we elucidated the expression and clinical significance of Homeobox A11 (HOXA11) in BC for the first time, and originally investigated HOXA11 as a TF. Employing in-house immunohistochemistry (IHC), we incorporated 137 BC and 34 non-BC cases to detect the expression of HOXA11 protein in BC tissues. HOXA11-related RNA-sequencing (RNA-seq) expression and RNA microarrays were collected from public databases, the "sva" and "limma" R packages were implemented to integrate and normalize the RNA-seq data and microarrays separately. Integration expression was carried out to further evaluate the HOXA11 expression by utilizing the standard mean difference (SMD). The expression level of HOXA11 in various BC cell lines was also evaluated. We further systematically analyzed the downstream target genes of HOXA11 in BC by utilizing Chromatin Immunoprecipitation Sequencing (ChIP-seq) profiles, differentially expressed genes (DEGs), and HOXA11-related genes. Modification of histone marks on the promoter region of target genes were also discovered by histone ChIP-seq data. Results of the IHC and RNA-seq revealed the protein and mRNA expression of HOXA11 was significantly decreased in BC tissues compared to non-BC tissues (2.98 ± 1.48 vs. 8.23 ± 2.64; 6.87 ± 1.54 vs. 8.38 ± 1.42). Five platforms significantly revealed the down-regulation of HOXA11 expression in BC (GPL96, GPL570, GPL6102, GPL6884, and GPL13497). A similar decreased trend was discovered in BC tissues in expression integration with the incorporated SMD reaching -0.843 (-1.362 ~ -0.325, p = 0.001) and -1.051 (-1.674 ~ -0.428, p = 0.001). Expression of HOXA11 was down-regulated in most of the BC cell lines. COL1A1 was considered as a final HOXA11 target gene and positively related to HOXA11 with the correlation coefficient as 0.584 (95% CI: 0.371-0.739, p < 0.001). HOXA11 regulates COL1A1 expression in BC via H3K27ac modification. The expression of COL1A1 was down-regulated with the SMD reached -0.312 (p < 0.001). In conclusion, HOXA11 expression is markedly decreased and might promote the transcription of COL1A1 to inhibit BC., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

BACKGROUND Bladder carcinoma (BLCA) is a leading cause of cancer-related deaths worldwide. The aim of this work was to develop an accurate stratification in predicting the prognosis and directing the treatment of BLCA patients based on small nucleolar RNAs (snoRNAs). MATERIAL AND METHODS Expression profiles of snoRNAs were downloaded from the SNORic database. The expression profiles and clinical outcomes of BLCA patients were analyzed. Survival-associated snoRNAs were identified and used to develop a novel risk score classifier. Genes in the whole genome that were significantly correlated with the included prognostic snoRNAs were used for functional enrichment analysis. RESULTS The results showed that age, American Joint Committee on Cancer (AJCC) stage, and tumor status were significantly correlated with overall survival (OS) of BLCA patients. We selected 12 survival-associated snoRNAs to build a prognostic signature. Patients were separated into high- and low-risk groups based on the median value of the risk score. Patients in the high-risk group and low-risk group have distinct clinical outcomes. The AJCC TNM stage showed moderate utility as a prognostic indicator for clinical outcome prediction. Then, clinical parameters and risk scores were entered in multivariate Cox analysis. Notably, the prognostic signature remained an independent significant prognostic risk factor. The pathway analysis suggested that these genes were enriched in several types of cancer and "Focal adhesion" pathways. CONCLUSIONS The prognostic signature defined by expression profiles of 12 survival-associated snoRNAs appears to be an excellent predictor of the clinical outcome of BLCA patients.