Carcinogenesis Of Bladder Cancer Research Articles

Circular RNA LMBR1 inhibits bladder cancer progression by enhancing expression of the protein ALDH1A3

BackgroundCircular RNAs (circRNAs) have been identified as playing an integral role in the development of bladder cancer (BC). However, the mechanism by which circRNAs operate in the chemical carcinogenesis of BC remains unclear. MethodsTo explore this mechanism, we used RNA high-throughput sequencing to identify differentially expressed circRNA in bladder epithelial cells and chemically induced malignant transformed BC cells. Subsequently, in vitro experiments were conducted to investigate the biological function and molecular mechanism of circLMBR1 in BC. Finally, animal experiments were conducted to examine the clinical relevance of circLMBR1 in vivo. ResultsOur profiling of circular RNA expression during cellular malignant transformation induced by chemical carcinogens identified a subset of circRNAs associated with cell transformation. We verified that the expression of circLMBR1 in bladder epithelial malignant transformed cells was decreased compared with control cells, as well as in BC tissues and bladder cell lines. Furthermore, circLMBR1 was seen to inhibit the proliferation, invasion, and migration of BC cells both in vitro and in vivo. Mechanistically, circLMBR1 was found to exert its antitumor effect by binding to the protein ALDH1A3. ConclusionsOur findings have revealed that circLMBR1 inhibits the progression of BC cells by binding to ALDH1A3 and upregulating its expression. As such, circLMBR1 serves as a promising predictor of BC and may provide a novel therapeutic target for the treatment of BC.

Integrative analysis of the bladder cancer from a cell cycle NCAM1 perspective at both single cell and bulk resolution.

Bladder cancer (BLCA) is a prevalent and deadly form of urinary cancer, and there is a need for effective therapies, particularly for muscle-invasive bladder cancer (MIBC). Cell cycle inhibitors show promise in restoring control of the cell cycle in BLCA cells, but their clinical prognosis evaluation is limited. Transcriptome and scRNA-seq data were collected from the Cancer Genome Atlas Program (TCGA)-BLCA and GSE190888 cohort, respectively. R software and the Seurat package were used for data analysis, including cell quality control, dimensionality reduction, and identification of differentially expressed genes. Genes related to the cell cycle were obtained from the genecards website, and a protein-protein interaction network analysis was performed using cytoscape software. Functional enrichment analysis, immune infiltration analysis, drug sensitivity analysis, and molecular docking were conducted using various tools and packages. BLCA cell lines were cultured and transfected for in vitro experimental assays, including RT-qPCR analysis, and CCK-8 cell viability assays. We identified 32 genes as independent risk or protective factors for BLCA prediction. Functional enrichment analysis revealed their involvement in cell cycle regulation, apoptosis, and various signaling pathways. Using these genes, we developed a nomogram for predicting BLCA survival, which displayed high prognosis stratification efficacy in BLCA patients. Four cell cycle associated key genes identified, including NCAM1, HBB, CKD6, and CTLA4. We also identified the main cell types in BLCA patients and investigated the functional differences between epithelial cells based on their expression levels of key genes. Furthermore, we observed a high positive correlative relationship between the infiltration of cancer-associated fibroblasts and the risk score value. Finally, we conducted in vitro experiments to demonstrate the suppressive role of NCAM1 in BLCA cell proliferation. These findings suggest that cell cycle associated genes could serve as potential biomarkers for predicting BLCA prognosis and may represent therapeutic targets for the development of more effective therapies. Hopefully, these findings provide valuable insights into the molecular mechanisms and potential therapeutic targets in BLCA from the perspective of cell cycle. Moreover, NCAM1 was a novel cell proliferation suppressor in the BLCA carcinogenesis.

Abstract 1471: A novel mouse model of upper tract urothelial carcinoma influenced by gut microbiota

Abstract Introduction & Objective: Recently, it has been revealed that bladder cancer (BC) and upper tract urothelial carcinoma (UTUC) are biologically distinct diseases. Mouse models of BC carcinogenesis have been established using N-butyl-N-(4-hydro-oxybutyl) nitorosamine (BBN) for a long time, but there are few reports of UTUC carcinogenesis with high incidence. Therefore, the UTUC carcinogenesis mouse model is expected. The aim of this study is to establish a novel mouse model of UTUC carcinogenesis and to identify the characteristics of this model. Methods: We used two strains (C57BL/6 and BALB/c) of male and female mice and fed 0.05% BBN from 6 weeks old to the harvest day. Both sides of upper urinary tract from mice drinking BBN or tap water were subjected to whole exome sequencing and whole transcriptome sequencing (WTS) to assess its genetic similarity to human UTUC. Microbiome in gut were assessed by 16S ribosomal RNA gene sequencing (16S rRNA-seq). Metabolic differences in feces, serum and liver between UTUC mice and healthy mice were evaluated by comprehensive metabolomic analysis. Inflammatory mediators were assessed by quantitative polymerase chain reaction (qPCR). Results: Only BALB/c female showed higher incidence of UTUC than BC, while the other strains rarely had UTUC. This model showed SBS5-like mutational pattern. The frequent mutated gene list showed similarity to human UTUC. In terms of gene expression, this model belonged basal subtype. We detected 593 differentially expressed genes between cancerous side and non-cancerous side of upper urinary tract in this model, which could also classify human UTUC and adjacent normal samples. The cancerous side of upper urinary tract enriched several inflammation related pathways such as Nfkb and Tnf pathway. We validated the upregulation of inflammatory gene expression in upper urinary tract (Il6, Il1b, Tnfa, Relb) by qPCR (all: p < 0.05). 16S rRNA-seq revealed that Firmicutes was enriched in feces. Metabolomic analysis revealed that some amino acids in feces and FAD in serum were upregulated. Feeding with amino acid mediated diet changed gut environment. Firmicutes in feces and FAD in both feces and serum were downregulated consistently. This diet suppressed inflammatory gene expression in upper urinary tract (Il6, Il1b, Tnfa, Relb, Cd38, Tnfrsf1b and Kdm1a; all: p < 0.05). Finally, UTUC was disappeared but not BC in this model treated by BBN with amino acid mediated diet. Conclusion: We have established a novel mouse model developing UTUC with high incidence that genetically mimics human UTUC. In addition, amino acid mediated diet can change both microbiome and metabolome in gut of this model, downregulate host’s inflammatory reaction to BBN in upper urinary trat and suppress the UTUC carcinogenesis. Citation Format: Akinaru Yamamoto, Atsunari Kawashima, Kentaro Jingushi, Sassi Nesrine, Yuki Horibe, Akihiro Yoshimura, Masaru Tani, Liu Yutong, toshiki Oka, Yohei Okuda, toshihiro Uemura, Gaku Yamamichi, Yu Ishizuya, Yoshiyuki Yamamoto, Taigo Kato, Koji Hatano, Norio Nonomura. A novel mouse model of upper tract urothelial carcinoma influenced by gut microbiota [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1471.

The Diagnostic and Therapeutic Role of snoRNA and lincRNA in Bladder Cancer

Bladder cancer is one of the most common malignancies of the urinary tract and can be divided into non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). Although the means of diagnosis and treatment have continually improved in recent years, the recurrence rate of bladder cancer remains high, and patients with MIBC typically have an unfavourable prognosis and a low quality of life. Emerging evidence demonstrates that long noncoding RNAs play a crucial role in the carcinogenesis and progression of bladder cancer. Long intergenic noncoding RNAs (lincRNAs) are a subgroup of long noncoding RNAs (lncRNAs) that do not overlap protein-coding genes. The potential role of lincRNAs in the regulation of gene expression has been explored in depth in recent years. Small nucleolar RNAs (snoRNAs) are a class of noncoding RNAs (ncRNAs) that mainly exist in the nucleolus, are approximately 60-300 nucleotides in length, and are hosted inside the introns of genes. Small nucleolar RNA host genes (SNHGs) have been associated with the origin and development of bladder cancer. In this review, we aim to comprehensively summarize the biological functions of these molecules in bladder cancer.

Smoking-related epigenetic modifications are associated with the prognosis and chemotherapeutics of patients with bladder cancer.

Epidemiologic studies have linked smoking to various malignancies, including bladder cancer, but its underlying biological functions remain elusive. Currently, we aimed to identify the smoking-related epigenetic modifications and disclose their impacts on prognosis and therapies in bladder cancer. DNA methylation, transcriptome, and clinical profiles were acquired from The Cancer Genome Atlas (TCGA) using "TCGAbiolinks" Differential expression analyses were performed with "limma" and visualized by the "pheatmap" package. Smoking-related interactions were displayed using Cytoscape. Least absolute shrinkage and selection operator (LASSO) algorithm was for generation of a smoking-related prognostic model. Kaplan-Meier analysis with log-rank test was for survival analysis, followed by a prognostic nomogram. The Gene Set Enrichment Analysis (GSEA) was used for functional analysis. The "oncoPredict" package was applied for drug sensitivity analysis. We recruited all types of bladder cancers and found that smoking was involved in poor prognosis, with the hazard ratio (HR) of 1.600 (95%CI: 1.028-2.491). A total of 1078 smoking-related DNA methylations (526 hypermethylation and 552 hypomethylation) were identified and 9 methylation-driven genes differentially expressed in bladder cancer. Also, 506lncRNAs (448 upregulated and 58 downregulated lncRNAs) and 102 miRNAs (74 upregulated and 28 downregulated miRNAs) were determined as smoking-related ncRNAs. We then calculated the smoking-related risk score and observed that cases of high risk were predicted with poor prognosis. We constructed a prognostic nomogram to predict the 1-, 3-, and 5-year overall survival rates. Several cancer-related pathways were enriched in the high-risk group, and patients with high-risk were more sensitive to Gemcitabine, Wnt-C59, JAK1_8709, KRAS (G12C) Inhibitor-12, and LY2109761. Whereas, those with low-risk were more sensitive to Cisplatin, AZ960, and Buparlisib. Totally, we initially identified the smoking-related epigenetic modifications in bladder cancer and constructed a corresponding prognostic model, which was also linked to disparate sensitivities to chemotherapeutics. Our findings would provide novel insights into the carcinogenesis, prognosis, and therapies in bladder cancer.

Construction of cuproptosis-related gene signature to predict the prognosis and immunotherapy efficacy of patients with bladder cancer through bioinformatics analysis and experimental validation.

Background: A new form of cell death, copper-dependent cell death (termed cuproptosis), was illustrated in a recent scientific study. However, the biological function or prognostic value of cuproptosis regulators in bladder cancer (BLCA) remains unknown. Materials and Methods: Sequencing data obtained from BLCA samples in TCGA and GEO databases were preprocessed for analysis. Biological function and immune cell infiltration levels evaluated by gene set variation analysis (GSVA) were employed to calculate enrichment scores. Iteration least absolute shrinkage and selection operator (LASSO) and COX regression model were employed to select feature genes and construct a novel cuproptosis-related (CR) score signature. The genomics of drug sensitivity in cancer (GDSC) and tumor immune dysfunction and exclusion (TIDE) analysis were used to predict the chemotherapy and immunotherapy efficacy for BLCA patients. The relative expression of the genes involved in the signature was also verified by real-time quantitative PCR (qRT-PCR) in cell lines and tissues. Results: Expression abundance and the prognostic value of cuproptosis regulators proved that cuproptosis might play a vital part in the carcinogenesis of BLCA. GSVA revealed that cuproptosis regulators might be associated with metabolism and metastasis-related pathways such as TGF-β, protein secretion, oxidative Phosphorylation, MYC targets, MTORC1, and adipogenesis pathways. CR scores could predict the prognosis and evaluate the chemotherapy and immunotherapy efficacies of BLCA. CR scores were positively correlated with EMT, MYC, MTORC1, HEDGEHOG, and E2F signaling pathways; meanwhile, they were negatively correlated with several immune cell infiltration levels such as CD8+ T cells, γδT cells, and activated dendritic cells. Several GEO datasets were used to validate the power of prognostic prediction, and a nomogram was also established for clinical use. The expressions of DDX10, RBM34, and RPL17 were significantly higher in BLCA cell lines and tissues in comparison with those in the corresponding normal controls. Conclusion: Cuproptosis might play an essential role in the progression of BLCA. CR scores could be helpful in the investigation of prognostic prediction and therapeutic efficacy and could make contributions to further studies in BLCA.

UCHL5 Promotes Proliferation and Migration of Bladder Cancer Cells by Activating c-Myc via AKT/mTOR Signaling.

Ubiquitin C-terminal hydrolase L5 (UCHL5) is a deubiquitinating enzyme (DUB) that removes ubiquitin from its substrates. Associations between UCHL5 and cancer have been reported in various tissues, but the effect of UCHL5 on bladder cancer has not been thoroughly investigated. This study investigates the expression and function of UCHL5 in bladder cancer. UCHL5 was shown to be abnormally expressed using IHC of tissue microarray and Western blotting. Several procedures were performed to assess the effect of UCHL5 overexpression or knockdown on bladder cancer, such as cell proliferation, colony formation, wound-healing, and Transwell assays. In addition, RNA-Seq and Western blotting experiments were used to verify the status of downstream signaling pathways. Finally, bladder cancers with knockdown or overexpression of UCHL5 were treated with either SC79 or LY294002 to examine the participation of the AKT/mTOR signaling pathway and the expression of downstream targets c-Myc, SLC25A19, and ICAM5. In contrast to adjacent tissue samples, we discovered that UCHL5 was substantially expressed in bladder cancer samples. We also found that UCHL5 downregulation significantly suppressed both tumor growth in vivo and cell proliferation and migration in vitro. According to RNA-Seq analyses and Western blotting experiments, the expression of c-Myc, SLC25A19, and ICAM5 was modified as a result of UCHL5 activating AKT/mTOR signaling in bladder cancer cells. All things considered, our findings show that increased UCHL5 expression stimulates AKT/mTOR signaling, subsequently triggering the expression of c-Myc, SLC25A19, and ICAM5, which in turn promotes carcinogenesis in bladder cancer. UCHL5 is therefore a potential target for therapy in bladder cancer patients.

Antifungal immunity mediated by C-type lectin receptors may be a novel target in immunotherapy for urothelial bladder cancer.

Immunotherapies, such as immune-checkpoint blockade and adoptive T-cell therapy, offer novel treatment options with good efficacy for patients with urothelial bladder cancer. However, heterogeneity and therapeutic resistance have limited the use of immunotherapy. Further research into immune-regulatory mechanisms in bladder cancer is urgently required. Emerging evidence demonstrates that the commensal microbiota and its interactions with host immunity play pivotal roles in a variety of physiological and pathological processes, including in cancer. The gut microbiota has been identified as a potentially effective target of treatment that can be synergized with immunotherapy. The urothelial tract is also a key site for multiple microbes, although the immune-regulatory role of the urinary microbiome in the process of carcinogenesis of bladder cancer remains to be elucidated. We performed a comprehensive analysis of the expression and biological functions of C-type lectin receptors (CLRs), which have been recognized as innate pathogen-associated receptors for fungal microbiota, in bladder cancer. In line with previous research on fungal colonization of the urothelial tract, we found that CLRs, including Dectin-1, Dectin-2, Dectin-3, and macrophage-inducible Ca2+-dependent lectin receptor (Mincle), had a significant association with immune infiltration in bladder cancer. Multiple innate and adaptive pathways are positively correlated with the upregulation of CLRs. In addition, we found a significant correlation between the expression of CLRs and a range of immune-checkpoint proteins in bladder cancer. Based on previous studies and our findings, we hypothesize that the urinary mycobiome plays a key role in the pathogenesis of bladder cancer and call for more research on CLR-mediated anti-fungal immunity against bladder cancer as a novel target for immunotherapy in urothelial bladder cancer.

Antioxidant status in patients with bladder cancer regarding cancer stage and grade

ObjectiveThe imbalance of antioxidants and pro-oxidants plays a crucial role in the carcinogenesis of bladder cancer (BC). This study aimed to evaluate serum antioxidant status in patients with BC and determine its potential use in the diagnosis and progression potential considerations following histopathological assessment. MethodsA cross-sectional study included 90 patients with BC, divided into Ta, T1, and T2–T4 stage subgroups, and according to cancer progression potential, into low-grade (LG) and high-grade (HG) subgroups. The control group (CG) included 30 healthy volunteers. Antioxidant status was determined using the spectrophotometric method and standard laboratory tests. ResultsSerum superoxide dismutase activity was significantly higher in BC patients regarding cancer stage in comparison to the CG (p<0.001). Catalase activity was highest in T2–T4 subgroup and was significantly higher compared to the Ta (p<0.01) and T1 (p<0.05) subgroups. Serum albumin level was significantly lower in the BC group compared to the CG (p<0.001). In addition, it was significantly lower in T2–T4 subgroup compared to T1 and Ta subgroups (p<0.01). A significant negative correlation was found between tumor size and serum albumin level only (r=−0.386, p<0.01). Catalase activity was higher in HG subgroup (p=0.009), while bilirubin level was higher in LG subgroup (p=0.035). The optimal cut-off value of catalase activity in differentiating patients with LG and HG BC subgroups was ≥11.96 IU/L, and the specificity and sensitivity were 51.1% and 82.2%, respectively. Bilirubin level, for a calculated optimal cut-off value of ≥11.95 μmol/L, had a specificity of 44.1% and sensitivity of 80.0%. ConclusionMore invasive stages of BC with greater progression potential are associated with an increase in enzymatic antioxidant activity and a decrease in non-enzymatic antioxidant capacity. It may suggest a possible role of antioxidants in the prediction and monitoring of illness trajectory.

SMARCC1 Enters the Nucleus via KPNA2 and Plays an Oncogenic Role in Bladder Cancer.

Background: SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily C member 1 (SMARCC1), a component of the SWI/SNF complex, is thought to be an oncogene in several kinds of cancer. Materials and methods: The potential interaction between SMARCC1 and KPNA2 was inquired by Spearman’s correlation analysis, immunofluorescence staining and co-immunoprecipitation (Co-IP) assays. The immunohistochemistry staining, RT-PCR and western blot assay were taken for determining the expression levels of SMARCC1. And CCK-8, transwell assay, cell apoptosis assay, cell cycle analysis and subcutaneous tumor model were conducted to explore the role of SMARCC1 in carcinogenesis of bladder cancer. Results: In our experiments, Spearman’s correlation analysis, immunofluorescence staining and co-immunoprecipitation (Co-IP) assays showed that SMARCC1 interacted with KPNA2, and after knockdown of KPNA2, Nup50 and Nup153, the nuclear content of SMARCC1 decreased while the amount of SMARCC1 protein remaining in the cytoplasm increased, indicating that SMARCC1 could be transported into the nucleus via KPNA2 and thus acted as an oncogene. We found that both the mRNA and protein expression levels of SMARCC1 were increased in bladder cancer, and increased SMARCC1 expression was significantly associated with a higher T stage and poorer prognosis in bladder cancer patients. Knockdown of SMARCC1 slowed the growth of the two tested cell lines and clearly arrested the cell cycle at the G0/G1 phase checkpoint. Moreover, the migratory ability was significantly decreased and the number of apoptotic cells was increased. Conclusion: On the whole, our results demonstrate KPNA2, Nup50 and Nup153 regulate the process of SMARCC1 nuclear translocation in BC. SMARCC1 may be a competent candidate as a diagnostic and therapeutic target for BC. Further studies are required to research the mechanism and assess the role of SMARCC1 in vivo.

Dynamic Changes in Myofibroblasts Affect the Carcinogenesis and Prognosis of Bladder Cancer Associated With Tumor Microenvironment Remodeling.

Bladder cancer (BLCA) is a tumor that possesses significant heterogeneity, and the tumor microenvironment (TME) plays an important role in the development of BLCA. The TME chiefly consists of tumor cells and tumor-infiltrating immune cells admixed with stromal components. Recent studies have revealed that stromal components, especially cancer-associated fibroblasts (CAFs), affect immune cell infiltration and modulate the extracellular matrix in the TME of BLCA, ultimately impacting the prognosis and therapeutic efficacy of BLCA. Among the subgroups of CAFs, myofibroblasts (myCAFs) were the most abundant and were demonstrated to play an essential role in affecting the prognosis of various tumors, including BLCA. However, the dynamic changes in myCAFs during carcinogenesis and tumor progression have been less discussed previously. With the help of bioinformatics algorithms, we discussed the roles of myCAFs in the carcinogenesis and prognosis of BLCA in this manuscript. Our study highlighted the pathogenesis of BLCA was accompanied by a decrease in the abundance of myCAFs, revealing potential protective properties of myCAFs in the carcinogenesis of BLCA. Meanwhile, the reduced expressions of myCAFs marker genes were highly accurate in predicting tumorigenesis. In contrast, we also demonstrated that myCAFs regulated extracellular matrix remodeling, tumor metabolism, cancer stemness, and oncological mutations, ultimately impacting the treatment responsiveness and prognosis of BLCA patients. Thus, our research revealed the bimodal roles of myCAFs in the development of BLCA, which may be associated with the temporal change of the TME. The in-depth study of myofibroblasts and the TME may provide potential diagnostic biomarkers and therapeutic targets for BLCA.

The Role of Circular RNAs in the Carcinogenesis of Bladder Cancer.

Circular RNAs (circRNAs) are a group of transcripts with enclosed configurations which can regulate gene expression. These transcripts have important roles in normal development and in the pathogenesis of disorders. Recent evidence has supported involvement of circRNAs in the development of bladder cancer. Several circRNAs such as circ_0058063, hsa-circRNA-403658, circPDSS1, circCASC15, circRNA-MYLK, and circRNA_103809 have been upregulated in bladder cancer samples. On the other hand, hsa_circ_0137606, BCRC-3, circFUT8, hsa_circ_001598, circSLC8A1, hsa_circ_0077837, hsa_circ_0004826, and circACVR2A are among downregulated circRNAs in bladder cancer. Numerous circRNAs have diagnostic or prognostic value in bladder cancer. In this review, we aim to outline the latest findings about the role of circRNAs in bladder cancer and introduce circRNAs for further investigations as therapeutic targets.

Dietary fats and their sources in association with the risk of bladder cancer: A pooled analysis of 11 prospective cohort studies.

The effects of fat intake from different dietary sources on bladder cancer (BC) risk remains unidentified. Therefore, the present study aimed to investigate the association between fat intakes and BC risk by merging world data on this topic. Data from 11 cohort studies in the BLadder cancer Epidemiology and Nutritional Determinants (BLEND) study, provided sufficient information on fat intake for a total of 2731 BC cases and 544 452 noncases, which yielded 5 400 168 person‐years of follow‐up. Hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were estimated using Cox‐regression models stratified on cohort. Analyses were adjusted for total energy intake in kilocalories, gender, smoking status (model‐1) and additionally for sugar and sugar products, beers, wine, dressing and plant‐based and fruits intakes (model‐2). Among women, an inverse association was observed between mono‐unsaturated fatty acids (MUFAs) and BC risk (HR comparing the highest with the lowest tertile: 0.73, 95% CI: 0.58‐0.93, P‐trend = .01). Overall, this preventative effect of MUFAs on BC risk was only observed for the nonmuscle invasive bladder cancer (NMIBC) subtype (HR: 0.69, 95% CI: 0.53‐0.91, P‐trend = .004). Among men, a higher intake of total cholesterol was associated with an increased BC risk (HR: 1.37, 95% CI: 1.16‐1.61, P‐trend = .01). No other significant associations were observed. This large prospective study adds new insights into the role of fat and oils in BC carcinogenesis, showing an inverse association between consumption of MUFAs and the development of BC among women and a direct association between higher intakes of dietary cholesterol and BC risk among men.

A study of the immunohistochemical profile of bladder cancer in neuro-urological patients by the French Association of Urology.

To establish whether the expression of markers of cell differentiation (CK7, CK14, CK20, GATA3), apoptosis (p53), proliferation (Ki67, STAG2) and peri-tumoural lymphocytes (CD3, CD8), provides specific information about urothelial carcinogenesis in neuro-urological patients with bladder cancer (NBC). Tissue samples from NBC were retrieved from 15 centres in France and compared to control samples from non neuro-urological patients with bladder cancer (NNBC) and from neuro-urological patients without bladder cancer (NB). The expression of CK7, CK14, CK20, GATA3, p53, Ki67, STAG2, CD3 and CD8 markers was analysed using immunohistochemistry of tissue microarray sections. Overall, tissue samples from 124 patients were included in the study (n = 72 NBC, n = 26 NNBC and n = 26 NB). Muscle invasive bladder cancer (MIBC) was found in 52 NBC patients (72.2%) and squamous cell differentiation in 9 (12.5%). In NBC samples, the expression of CK20 and GATA3 was significantly more frequent in NMIBC compared to MIBC (p = 0.015 and p = 0.004, respectively). CK20 and GATA3 were significantly more expressed in NBC compared to NNBC (p < 0.001 and p = 0.010, respectively). The expression of CK14, Ki67, CD3 and CD8 was significantly more frequent in NBC than in NNBC samples (p = 0.005, p < 0.001, p < 0.001 and p < 0.001, respectively). The expression of CD3 and CD8 was similar in NBC and NB samples. In NBC, markers of basal differentiation, proliferation and peri-tumoural lymphocytes were significantly more expressed compared to NNBC controls. These results suggest the aggressiveness of NBC and the role of chronic inflammation in the carcinogenesis of bladder cancer in neuro-urological patients.

The role of herpes and human papillomavirus infection in prostate and bladder carcinogenesis

Human papillomavirus (HPV) is a small epithelial, non-enveloped, double-stranded DNA virus that belongs to the Papillomaviridae family. HPV infection is one of the most common sexually transmitted infections, and certain types of HPV are known to be carcinogenic to humans. According to the scientific literature, there is reliable information about the role of highly oncogenic HPV types in the development of cervical, anal, vulvar, vaginal, penile, and oropharyngeal cancer.Currently, a relevant and promising research area is the study of the role of HPV infection in prostate cancer (PC) and bladder cancer (BC), but scientific data on the potential pathogenetic relationship between these phenomena remain contradictory. An in-depth study of the question how herpes and human papillomavirus affect the origin of malignant tumors of the prostate and bladder, as well as the course of these diseases, and the prognosis of their development can become a source of information for development of new approaches to their diagnosis, prevention, and monitoring of morbidity. This literature review analyzes the results of modern studies on the role of oncogenic HPV types in the carcinogenesis of PC and BC.

Comprehensive analysis of CXCL12 expression reveals the significance of inflammatory fibroblasts in bladder cancer carcinogenesis and progression

BackgroundBladder cancer (BLCA) is the most common genitourinary tumor but lacks specific diagnostic biomarkers. Recent years have witnessed significant advances in the use and approval of immune checkpoint blockade (ICB) therapy to manage BLCA at advanced stages when platinum-based therapy has failed. The tumor microenvironment (TME) is essential in impacting BLCA patients' prognosis and responsiveness to ICB therapy. CXCL12 is a stromal secreted factor that was essentially involved in regulating the TME among cancers. In this article, we thoroughly investigated the TME regulating roles of CXCL12 in BLCA and revealed its critical involvement in the development of BLCA, which was closely correlated with inflammatory fibroblasts (iCAFs).MethodsWe examined the gene expression profiles in the TCGA and GEO database to reveal the potential association of CXCL12 with the carcinogenesis and prognosis of BLCA. The receiver operating characteristic curve was used to explore the accuracy of CXCL12 along with multiple iCAFs-associated genes in the diagnosis of BLCA. The MCP-COUNTER, ESTIMATE, and TIDE algorithms were applied to estimate the TME components and predict immunotherapy responsiveness. An iCAFs signature was constructed using the ssGSEA algorithm. The "maftool" R package analyzed the oncogenic mutations in BLCA patients. Bioinformatics analysis results were further validated through immunohistochemistry of clinical samples. IMvigor210 cohort was used to validate bioinformatic predictions of therapeutic responsiveness to immune checkpoint inhibitors.ResultsThis manuscript revealed a significantly reduced expression of CXCL12 in BLCA compared with normal tissue. The expressions of various marker genes for iCAFs were also reduced considerably in BLCA tissues, highlighting the reduction of iCAFs in the pathogenesis of BLCA. Further studies revealed that CXCL12 and iCAFs were associated with pathological features, TME remodeling and aging in BLCA patients. The iCAFs signature further confirmed the intricate immunomodulatory roles of iCAFs in BLCA. Gene mutation analysis revealed the essential relationship between iCAFs and the mutation frequency of oncogenic genes, including TP53 and FGFR3. Meantimes, iCAFs levels also significantly affected BLCA patients' mutations in the TP53 and RTK-RAS pathways. Finally, our results confirmed the significant exclusion of CD8 + T cells by iCAFs, which further influenced the immunotherapy responsiveness in BLCA patients.ConclusionsThis article highlighted the impact of CXCL12 on the pathogenesis and progression of BLCA. The reduced expression levels of iCAFs markers, including CXCL12, were highly accurate in the diagnosis of BLCA, suggesting the reduction of iCAFs accompanied bladder carcinogenesis. However, both CXCL12 and iCAFs significantly impacted the prognosis and immunotherapy responsiveness for BLCA patients by remodeling the TME. Our results critically suggested the dual roles of iCAFs in the carcinogenesis and progression of BLCA. Further exploration of iCAFs might unravel potential diagnostic biomarkers and therapeutic targets for BLCA.

LINC00958 promotes bladder cancer carcinogenesis by targeting miR-490-3p and AURKA

BackgroundBladder cancer is a prevalent malignancy of the urinary system, in which long non-coding RNAs (lncRNAs) are highly associated. We aimed to elucidate the role of LINC00958 in bladder cancer.MethodsLINC00958 expression levels were measured using qRT-PCR. The interaction of LINC00958-miR-490-3p-AURKA was analyzed by luciferase, RIP, and RNA pull-down assays. The biological roles of LINC00958, miR-490-3p, and AURKA in bladder cancer cells were analyzed using CCK8, BrdU, and transwell assays.ResultsIncreased expression of LINC00958 and AURKA was observed in bladder cancer tissues and cell lines. Decreased LINC00958 expression repressed bladder cancer progression and downregulation of miR-490-3p accelerated bladder cancer cell progression. Moreover, LINC00958 sponges miR-490-3p to upregulate AURKA expression, thereby promoting carcinogenesis in bladder cancer cells.ConclusionsOur study revealed that LINC00958 facilitated cell proliferation and invasion, and suppressed cell apoptosis by sponging miR-490-3p and upregulating AURKA, thus inspiring a new treatment method for bladder cancer.

Ceruloplasmin Levels in Cancer Tissues and Urine Are Significant Biomarkers of Pathological Features and Outcome in Bladder Cancer.

A previous report showed that immune complex-ceruloplasmin (CP) in urine is associated with carcinogenesis and malignant behavior in bladder cancer (BC). We investigated the pathological significance and prognostic roles of urine and tissue levels of CP protein in BC patients. Urine CP levels were measured using an enzyme-linked immunosorbent assay in 97 patients. CP expression in BC tissues was evaluated by immunohistochemical analysis in 176 patient samples. Urine CP levels were positively associated with tumor grade and pT stage in non-muscle invasive BC (NMIBC). CP expression in BC tissues was positively associated with tumor growth and progression. Multivariate analysis demonstrated that high urine CP levels was an independent predictor of recurrence in the urinary tract in NMIBC (hazard ratio=2.87, p=0.016). CP-related markers, especially urine CP levels, are useful biomarkers of malignant potential and prognosis in NMIBC.

New Insights into the Diagnosis, Molecular Taxonomy, and Treatment of Bladder Cancer.

This review aims to emphasize new insights into the diagnosis, classification, and therapy of bladder cancer (BC). Bladder cancer is a heterogeneous, complex disease on a morphological, molecular, diagnostic, and prognostic level. Cancer stage is still the most important attribute for prognosis and treatment, while early detection with optimal and rapid individual therapeutic and surveillance approach is crucial. The vast majority of patients have a superficial, non-muscle-invasive tumor associated with a good prognosis after resection and adjuvant intravesical maintenance immuno or chemotherapy if needed. On the other hand, muscle-invasive bladder cancer is a highly aggressive disease with high morbidity and mortality. However, it has become a model for oncology success over the last five years with many available targeted therapeutic modalities. Metastatic BC is now amenable to multimodal treatment combining cystectomy and neoadjuvant chemotherapy and immunotherapy and is a target for precision medicine. CONCLUSION: A new molecular taxonomy for bladder cancer has been proposed and provided insight into BC's carcinogenesis, with some possible effects on therapy decisions. However, this classification is still not applicable in routine clinical practice. It opens new questions regarding the interplay between tumor genetic signature, intratumoral heterogeneity, therapy implications, and tumor progression.

MicroRNAs: Their Role in Metastasis, Angiogenesis, and the Potential for Biomarker Utility in Bladder Carcinomas.

Simple SummaryIn cells possessing invasive or metastatic capabilities, several classes of proteins that are involved in the tethering of cells to their surroundings are altered. Loss of cell–cell and cell–matrix adhesions, proteolysis, and induction of angiogenesis are all processes that allow the development of cancer invasion and metastasis. Additionally, epithelial mesenchymal transition (EMT) is a major contributor to the aggressive behavior of cells responsible for invasive growth and metastasis. Here we cover the roles of a few microRNAs (miRNAs) on the molecules that have been shown to play a significant role in bladder cancer metastasis and angiogenesis. These miRNAs could be considered as therapeutic modalities or as diagnostic biomarkers in future research.Angiogenesis is the process of generating new capillaries from pre-existing blood vessels with a vital role in tumor growth and metastasis. MicroRNAs (miRNAs) are noncoding RNAs that exert post-transcriptional control of protein regulation. They participate in the development and progression of several cancers including bladder cancer (BLCA). In cancer tissue, changes in microRNA expression exhibit tissue specificity with high levels of stability and detectability. miRNAs are less vulnerable to degradation, making them novel targets for therapeutic approaches. A suitable means of targeting aberrant activated signal transduction pathways in carcinogenesis of BLCA is possibly through altering the expression of key miRNAs that regulate them, exerting a strong effect on signal transduction. Precaution must be taken, as the complexity of miRNA regulation might result in targeting several downstream tumor suppressors or oncogenes, enhancing the effect further. Since exosomes contain both mRNA and miRNA, they could therefore possibly be more effective in targeting a recipient cell if they deliver a specific miRNA to modify the recipient cell protein production and gene expression. In this review, we discuss the molecules that have been shown to play a significant role in BLCA tumor development. We also discuss the roles of various miRNAs in BLCA angiogenesis and metastasis. Advances in the management of metastatic BLCA have been limited; miRNA mimics and molecules targeted at miRNAs (anti-miRs) as well as exosomes could serve as therapeutic modalities or as diagnostic biomarkers.