Development Of Bladder Cancer Research Articles

Identification and preliminary analysis of hub genes associated with bladder cancer progression by comprehensive bioinformatics analysis

Bladder cancer (BC) is a crisis to human health. It is necessary to understand the molecular mechanisms of the development and progression of BC to determine treatment options. Publicly available expression data were obtained from TCGA and GEO databases to spot differentially expressed genes (DEGs) between cancer and normal bladder tissues. Weighted co-expression networks were constructed, and Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Associations in hub genes, immune infiltration, and immune therapy were evaluated separately. Protein–protein interaction (PPI) networks for the genes identified in the normal and tumor groups were launched. 3461 DEGs in the TCGA dataset and 1069 DEGs in the GSE dataset were identified, including 87 overlapping genes between cancer and normal bladder groups. Hub genes in the tumor group were mainly enriched for cell proliferation, while hub genes in the normal group were related to the synthesis and secretion of neurotransmitters. Based on survival analysis, CDH19, RELN, PLP1, and TRIB3 were considerably associated with prognosis (P < 0.05). CDH19, RELN, PLP1, and TRIB3 may play important roles in the development of BC and are potential biomarkers in therapy and prognosis.

Expression, Prognostic Value, and Immune Infiltration of MTHFD Family in Bladder Cancer.

The Methylenetetrahydrofolate Dehydrogenase (MTHFD) family plays an important role in the development and prognosis of a variety of tumors; however, the role of the MTHFD family in bladder cancer is unclear. R software, cBioPortal, GeneMANIA, and online sites such as String-LinkedOmics were used for bioinformatics analysis. MTHFD1/1L/2 was significantly upregulated in bladder cancer tissues compared with normal tissues, high expression of the MTHFD family was strongly associated with poorer clinical grading and staging, and bladder cancer patients with upregulated expression of MTHFD1L/2 had a significantly worse prognosis. Gene function and PPI network analysis revealed that the MTHFD family and related genes play synergistic roles in the development of bladder cancer. 800 co-expressed genes related to the MTHFD family were used for functional enrichment analysis, and the results showed that many genes were associated with various oncogenic pathways such as cell cycle and DNA replication. More importantly, the MTHFD family was closely associated with multiple infiltrating immune lymphocytes, including Treg cells, and immune molecules such as TNFSF9, CD274, and PDCD1. Our study shows that MTHFD family genes may be potential prognostic markers and therapeutic targets for patients with bladder cancer.

Genomic profiling of bladder cancer in waterpipe and cigarette smokers: Implications for carcinogenicity and genetic landscape.

657 Background: While cigarette smoking is a well-established risk factor for bladder cancer (BC), limited research has explored the contribution of waterpipe smoking (WPS) to BC. WPS is gaining popularity among Middle Eastern youth, often perceived as a safer alternative to cigarettes. Alarmingly, Lebanese males had an age-standardized incidence rate of 54.0 per 100,000 in 2019, the highest in the Arab World and five times the global average, prompting a critical investigation into potential risk factors. Mounting evidence suggests that WPS exposes users to toxicants and carcinogens that can induce chromosomal damage contributing to cancer. This study aims to assess the genomic and mutational profiles of BC in waterpipe smokers compared to cigarette smokers. Methods: This cross-sectional study enrolled adults with urothelial carcinoma (UC) who exclusively smoked waterpipe at the American University of Beirut Medical Center (AUBMC) between April 2017 and September 2019. Next-generation sequencing by MSK-IMPACT characterized mutational profiles, tumor mutation burden, and microsatellite instability (MSI) status in tumor-normal pairs. For comparison, a cohort from Memorial Sloan Kettering Cancer Center (MSKCC), comprising previously profiled BC tumors from cigarette smokers, was used. Results: A total of 14 exclusively WPS-BC patients were enrolled, with 12 males (85.7%) and a median age at diagnosis of 62.9 years (range: 30.7 to 78.9). Among these patients, 9 (64.3%) had non-muscle invasive BC, with 8 (57.2%) classified as high-grade UC. MSK-IMPACT sequencing successfully analyzed 13 WPS samples, revealing genomic patterns similar to the cigarette smoking cohort. Common genetic alterations in the WPS cohort included mutations in TERT promoter (62%), TP53 and FGFR3 (46% each), and PIK3CA (38%). Mutations in chromatin modifiers were less prevalent, with the highest frequencies observed in KDM6A (31%) and KMT2C (15%). The tumor mutation burden was higher in the WPS group (22 per MB) compared to the cigarette smoking cohort (9 per MB), with no definite evidence of MSI. PD-L1 expression was generally low, with only 2 samples exhibiting combined positivity scores (CPS) of 15 and 10, primarily associated with immune cells PD-L1 expression. Only one tumor demonstrated 3% PD-L1 expression on tumor cells, while 7 tumors displayed no expression on either tumor or immune cells (CPS of 0). Conclusions: This study underscores the genomic similarities between BC in waterpipe and cigarette smokers. The preliminary findings, limited by sample size, highlight the need for further investigations to elucidate the potential role of WPS in BC development. Future efforts will focus on cohort expansion to validate initial observations, raising awareness of health risks associated with WPS, and emphasizing the importance of continued research to inform preventive strategies.

Association of ARID1A deficiency with invasive transformation in metastatic bladder cancer.

656 Background: ARID1A is an essential component of the BAF complex, a large SWI/SNF chromatin-remodeling complex which is implicated in bladder cancer (BC) pathogenesis. While ARID1A mutations are more highly represented in metastatic rather than localized tumors, the biological consequences of ARID1A loss in BC remain to be elucidated. We hypothesize that ARID1A deficiency primes an invasive transformation in BC, thus increasing the likelihood of disease progression and metastases. We used CRISPR/Cas9-mediated gene editing to knockout (KO) the ARID1A gene in several BC cell lines, thus providing a platform for cellular function assays. We show that ARIDA1 loss potentiates an invasive phenotype in these cell lines, giving evidence for its transformative role in the development of higher stage and metastatic BC. Methods: A CRISPR-Cas9 KO was performed with three cell lines with wild-type (WT) ARID1A (T24, SW1710, and 5637). This was accomplished by developing sgRNAs against ARID1A with a GFP marker and carrying out single-cell fluorescence-activated cell sorting (FACS) following nucleofection to identify ARID1A-deficient clones. Western blot analysis was performed on the resulting clones to confirm complete loss of ARID1A. Baseline proliferation studies were performed on the KO and WT cell lines. Finally, invasion studies were performed on the KO and WT cells with a scratch assay. Results: CRISPR-Cas9 directed KO of ARID1A yielded ARID1A-deficient clones for SW1710, T24, and 5637. The proliferation rates for each cell line were analyzed and compared which showed no significant differences. A scratch assay was performed with the cell lines in triplicate, with each ARID1A-deficient cell line showing a trend towards more rapid wound closure than its matched WT cell line (WT=31.5% vs. KO=53.5% for SW1710, p=0.15; WT=17.2% vs. KO=52.0% for T24, p=0.07; WT=10.4% vs. KO=13.9% for 5637, p=0.59). Conclusions: To explore the increased frequency of ARID1A alterations in metastatic BC compared to non-invasive tumors, we developed a model of ARID1A-deficient BC using CRISPR-Cas9. We compared the relative invasiveness of the lines using a scratch assay. All lines trended towards a more invasive phenotype following ARID1A KO, which was especially pronounced in T24. Taken together, these data suggest that ARID1A deficiency in BC may prime tumors for a more invasive phenotype, which may help to explain the higher frequency of ARID1A alterations in higher stage and metastatic samples.

The Urinary Microbiome in Health and Disease: Relevance for Bladder Cancer.

Bladder cancer (BC) constitutes one of the most diagnosed types of cancer worldwide. Advancements in and new methodologies for DNA sequencing, leading to high-throughput microbiota testing, have pinpointed discrepancies in urinary microbial fingerprints between healthy individuals and patients with BC. Although several studies suggest an involvement of microbiota dysbiosis in the pathogenesis, progression, and therapeutic response to bladder cancer, an established direct causal relationship remains to be elucidated due to the lack of standardized methodologies associated with such studies. This review compiles an overview of the microbiota of the human urinary tract in healthy and diseased individuals and discusses the evidence to date on microbiome involvement and potential mechanisms by which the microbiota may contribute to the development of BC. We also explore the potential profiling of urinary microbiota as a biomarker for risk stratification, as well as the prediction of the response to intravesical therapies and immunotherapy in BC patients. Further investigation into the urinary microbiome of BC patients is imperative to unravel the complexities of the role played by host-microbe interactions in shaping wellness or disease and yield valuable insights into and strategies for the prevention and personalized treatment of BC.

Squalene monooxygenase facilitates bladder cancer development in part by regulating PCNA

Bladder cancer (BC) is one of the most common cancers worldwide. Although the treatment and survival rate of BC are being improved, the risk factors and the underlying mechanisms causing BC are incompletely understood. Squalene monooxygenase (SQLE) has been associated with the occurrence and development of multiple cancers but whether it contributes to BC development is unclear. In this study, we performed bioinformatics analysis on paired BC and adjacent non-cancerous tissues and found that SQLE expression is significantly upregulated in BC samples. Knockdown of SQLE impairs viability, induces apoptosis, and inhibits the migration and invasion of BC cells. RNA-seq data reveals that SQLE deficiency leads to dysregulated expression of genes regulating proliferation, migration, and apoptosis. Mass spectrometry-directed interactome screening identifies proliferating cell nuclear antigen (PCNA) as an SQLE-interacting protein and overexpression of PCNA partially rescues the impaired viability, migration, and invasion of BC cells caused by SQLE knockdown. In addition, we performed xenograft assays and confirmed that SQLE deficiency inhibits BC growth in vivo. In conclusion, these data suggest that SQLE promotes BC development and SQLE inhibition may be therapeutically useful in BC treatment.

Machine learning algorithms predicting bladder cancer associated with diabetes and hypertension: NHANES 2009 to 2018.

Bladder cancer is 1 of the 10 most common cancers in the world. However, the relationship between diabetes, hypertension and bladder cancer are still controversial, limited study used machine learning models to predict the development of bladder cancer. This study aimed to explore the association between diabetes, hypertension and bladder cancer, and build predictive models of bladder cancer. A total of 1789 patients from the National Health and Nutrition Examination Survey were enrolled in this study. We examined the association between diabetes, hypertension and bladder cancer using multivariate logistic regression model, after adjusting for confounding factors. Four machine learning models, including extreme gradient boosting (XGBoost), Artificial Neural Networks, Random Forest and Support Vector Machine were compared to predict for bladder cancer. Model performance was assessed by examining the area under the subject operating characteristic curve, accuracy, recall, specificity, precision, and F1 score. The mean age of bladder cancer group was older than that of the non-bladder cancer (74.4 years vs 65.6 years, P < .001), and men were more likely to have bladder cancer. Diabetes was associated with increased risk of bladder cancer (odds ratio = 1.24, 95%confidence interval [95%CI]: 1.17-3.02). The XGBoost model was the best algorithm for predicting bladder cancer; an accuracy and kappa value was 0.978 with 95%CI:0.976 to 0.986 and 0.01 with 95%CI:0.01 to 0.52, respectively. The sensitivity was 0.90 (95%CI:0.74-0.97) and the area under the curve was 0.78. These results suggested that diabetes is associated with risk of bladder cancer, and XGBoost model was the best algorithm to predict bladder cancer.

Cigarette smoking combined with genetic variation regulates the m6A methylation of CRNKL1 and is associated with bladder cancer risk.

Cigarette smoking was known to accelerate the occurrence and development of bladder cancer by regulating RNA modification. However, the association between the combination of cigarette smoking and RNA modification-related single nucleotide polymorphisms (RNAm-SNPs) and bladder cancer risk remains unclear. In this study, 1681 participants, including 580 cases and 1101 controls, were recruited for genetic association analysis. In total, 1 287 990 RNAm-SNPs involving nine RNA modifications (m6A, m1A, m6Am, 2'-O-Me, m5C, m7G, A-to-I, m5U, and pseudouridine modification) were obtained from the RMVar database. The interactive effect of cigarette smoking and RNAm-SNPs on bladder cancer risk was assessed through joint analysis. The susceptibility analysis revealed that 89 RNAm-SNPs involving m6A, m1A, and A-to-I modifications were associated with bladder cancer risk. Among them, m6A-related rs2273058 in CRNKL1 was associated with bladder cancer risk (odds ratios (OR) = 1.35, padj = 1.78 × 10-4), and CRNKL1 expression was increased in bladder cancer patients (p = 0.035). Cigarette smoking combined with the A allele of rs2273058 increased bladder cancer risk compared with nonsmokers with the G allele of rs2273058 (OR = 2.40, padj = 3.11 × 10-9). Mechanistically, the A allele of rs2273058 endowed CRNKL1 with an additional m6A motif, facilitating recognition by m6A reader IGF2BP1, thereby promoting CRNKL1 expression under cigarette smoking (r = 0.142, p = 0.017). Moreover, elevated CRNKL1 expression may accelerate cell cycle and proliferation, thereby increasing bladder cancer risk. In summary, our study demonstrated that cigarette smoking combined with RNAm-SNPs contributes to bladder cancer risk, which provides a potential target for bladder cancer prevention.

Relevance of HOTAIR rs920778 and rs12826786 Genetic Variants in Bladder Cancer Risk and Survival.

The long non-coding RNA HOX transcript antisense intergenic RNA (HOTAIR) is associated with oncogenic features in bladder cancer and is predictive of poor clinical outcomes in patients diagnosed with this disease. In this study, we evaluated the impact of the HOTAIR single nucleotide polymorphisms rs920778 and rs12826786 on bladder cancer risk and survival. This case-control study included 106 bladder cancer patients and 199 cancer-free controls. Polymorphisms were evaluated through PCR-restriction fragment length polymorphism. The odds ratio and 95% confidence intervals were tested using univariable and multivariable logistic regressions. The effects on patient survival were evaluated using the log-rank test and Cox regression models. Our data showed that the HOTAIR rs920778 and rs12826786 genetic variants are not associated with the risk of developing bladder cancer. Nevertheless, survival analyses suggested that the HOTAIR rs920778 TT genotype and rs12826786 CC genotype are associated with increased survival in male bladder cancer patients and in patients, both male and female, who have primary tumors with a pathological stage of pT2. Together, these results suggest that, despite not being associated with bladder cancer risk, HOTAIR rs920778 and rs12826786 polymorphisms might represent new prognostic factors in this type of cancer. This is particularly important as these polymorphisms might be easily evaluated in bladder cancer patients in a minimally invasive manner to better predict their clinical outcomes.

Urinary Microbiome Dysbiosis and Immune Dysregulations as Potential Diagnostic Indicators of Bladder Cancer.

There are a total of 82,290 new cases and 16,710 deaths estimated for bladder cancer in the United States in 2023. Currently, urine cytology tests are widely used for bladder cancer diagnosis, though they suffer from variable sensitivity, ranging from 45 to 97%. More recently, the microbiome has become increasingly recognized for its role in human diseases, including cancers. This study attempts to characterize urinary microbiome bladder cancer-specific dysbiosis to explore its diagnostic potential. RNA-sequencing data of urine samples from patients with bladder cancer (n = 18) and matched controls (n = 12) were mapped to bacterial sequences to yield species-level abundance approximations. Urine samples were analyzed at both the population and species level to reveal dysbiosis associated with bladder cancer. A panel of 35 differentially abundant species was discovered, which may be useful as urinary biomarkers for this disease. We further assessed whether these species were of similar significance in a validation dataset (n = 81), revealing that the genera Escherichia, Acinetobacter, and Enterobacter were consistently differentially abundant. We discovered distinct patterns of microbial-associated immune modulation in these samples. Several immune pathways were found to be significantly enriched with respect to the abundance of these species, including antigen processing and presentation, cytosolic DNA sensing, and leukocyte transendothelial migration. Differential cytokine activity was similarly observed, suggesting the urinary microbiome's correlation to immune modulation. The adherens junction and WNT signaling pathways, both implicated in the development and progression of bladder cancer, were also enriched with these species. Our findings indicate that the urinary microbiome may reflect both microbial and immune dysregulations of the tumor microenvironment in bladder cancer. Given the potential biomarker species identified, the urinary microbiome may provide a non-invasive, more sensitive, and more specific diagnostic tool, allowing for the earlier diagnosis of patients with bladder cancer.

Modulation of tumor microenvironment by targeting histone acetylation in bladder cancer

Alterations in the epigenetic machinery in both tumor and immune cells contribute to bladder cancer (BC) development, constituting a promising target as an alternative therapeutic option. Here, we have explored the effects of a novel histone deacetylase (HDAC) inhibitor CM-1758, alone or in combination with immune checkpoint inhibitors (ICI) in BC. We determined the antitumor effects of CM-1758 in various BC cell lines together with the induction of broad transcriptional changes, with focus on the epigenetic regulation of PD-L1. Using an immunocompetent syngeneic mouse model of metastatic BC, we studied the effects of CM-1758 alone or in combination with anti-PD-L1 not only on tumor cells, but also in the tumor microenvironment. In vitro, we found that CM-1758 has cytotoxic and cytostatic effects either by inducing apoptosis or cell cycle arrest in BC cells at low micromolar levels. PD-L1 is epigenetically regulated by histone acetylation marks and is induced after treatment with CM-1758. We also observed that treatment with CM-1758 led to an important delay in tumor growth and a higher CD8 + T cell tumor infiltration. Moreover, anti-PD-L1 alone or in combination with CM-1758 reprogramed macrophage differentiation towards a M1-like polarization state and increased of pro-inflammatory cytokines systemically, yielding potential further antitumor effects. Our results suggest the possibility of combining HDAC inhibitors with immunotherapies for the management of advanced metastatic BC.

Understanding bladder cancer risk: Mendelian randomization analysis of immune cell and inflammatory factor influence.

The intricate roles of immune cells and inflammatory factors in cancer, particularly their association with the risk of bladder cancer, are not well understood. This study aimed to clarify potential causal relationships between these elements and the development of bladder cancer using genome-wide association study (GWAS) summary statistics for 731 immune cell phenotypes and 91 circulating inflammatory factors (cases=2,053; controls=287,137). The primary analytical approach was Inverse Variance Weighting (IVW), supplemented by MR-Egger regression, weighted median, and weighted mode analyses. Sensitivity analyses included Cochran Q test, MR-Egger intercept test, and Leave-one-out test. The findings indicated that monocytes are positively correlated with an increased risk of bladder cancer. On the contrary, double-negative (DN) T cells, HLA DR+CD8br, and CD28 on CD28+CD45RA+CD8br T cells exhibited an inverse correlation, suggesting a possible protective effect. Furthermore, inflammatory factors IL-20, IL-22RA1, and Eotaxin were significantly associated with an increased risk of bladder cancer. These results suggest that certain immune cell phenotypes and inflammatory factors may play a role in the development of bladder cancer and could serve as potential biomarkers for assessing tumor risk. The findings also offer new insights into the pathogenesis of bladder cancer, indicating a need for further investigation.

The Long-Term Impact of 5-alpha Reductase Inhibitors on the Development of Bladder Cancer and the Need for Radical Cystectomy: A Nationwide Observational Study.

To investigate the long-term effects of taking 5-alpha reductase inhibitors (5ARIs) on the development of bladder cancer (BC) and the implementation of radical cystectomy (RC), a standard procedure for advanced BC. From the National Health Insurance Sharing Service database, males aged over 40 years who underwent serum prostate-specific antigen testing from 2006 through 2017 were identified, which is required for the prescription of 5ARIs. The association between the administration duration of 5ARIs and the practice for BC was analyzed. Of the 3,843,968 subjects, 1,514,713 (39.4%) took 5ARIs for an average of 1.53 years, remaining 2,329,255 (60.6%) as non-5ARI counterparts. The incidence of BC was higher in the non-5ARI than in the 5ARI group (1.25% vs. 0.87%, p<0.001), as was the implementation rate of RC (11.1% vs. 10.4%, p=0.037). In a multivariate analysis, the non-5ARI group had a significant risk of BC (hazard ratio [HR]=2.289, 95% confidence interval [CI]=2.241-2.338) and RC (HR=2.199, 95% CI=2.061-2.348) than the 5ARI group. Among the 5ARIs group, though the incidence of BC was maintained (slope=-0.002 per year, p=0.79) after an initial increase for two years, the rate of RC decreased (slope=-1.1, p<0.001) consistently for ten years during the administration. Compared to the untreated group, 5ARIs use was associated with lower rates of BC and RC. In contrast to the increase in BC seen with short-term use of less than two years, long-term use of 5ARIs decreased the rate of RC in a duration-dependent manner for ten years, suggesting a strategy to prevent disease progression.

Alternative splicing regulation and its therapeutic potential in bladder cancer.

Bladder cancer is one of the leading causes of mortality globally. The development of bladder cancer is closely associated with alternative splicing, which regulates human gene expression and enhances the diversity of functional proteins. Alternative splicing is a distinctive feature of bladder cancer, and as such, it may hold promise as a therapeutic target. This review aims to comprehensively discuss the current knowledge of alternative splicing in the context of bladder cancer. We review the process of alternative splicing and its regulation in bladder cancer. Moreover, we emphasize the significance of abnormal alternative splicing and splicing factor irregularities during bladder cancer progression. Finally, we explore the impact of alternative splicing on bladder cancer drug resistance and the potential of alternative splicing as a therapeutic target.

Establishment of a SUMO pathway related gene signature for predicting prognosis, chemotherapy response and investigating the role of EGR2 in bladder cancer.

Background: Bladder cancer is a prevalent malignancy with significant clinical implications. Small Ubiquitin-like Modifier (SUMO) pathway related genes (SPRG) have been implicated in the development and progression of cancer. Methods: In this study, we conducted a comprehensive analysis of SPRG in bladder cancer. We analyzed gene expression and prognostic value of SPRG and developed a SPRG signature (SPRGS) prognostic model based on four genes (HDAC4, TRIM27, EGR2, and UBE2I) in bladder cancer. Furthermore, we investigated the relationship between SPRGS and genomic alterations, tumor microenvironment, chemotherapy response, and immunotherapy. Additionally, we identified EGR2 as a key SPRG in bladder cancer. The expression of EGR2 in bladder cancer was detected by immunohistochemistry, and the cell function experiment clarified the effect of knocking down EGR2 on the proliferation, invasion, and migration of bladder cancer cells. Results: Our findings suggest that SPRGS hold promise as prognostic markers and predictive biomarkers for chemotherapy response and immunotherapy efficacy in bladder cancer. The SPRGS prognostic model exhibited high predictive accuracy for bladder cancer patient survival. We also observed correlations between SPRG and genomic alterations, tumor microenvironment, and response to chemotherapy. Immunohistochemical results showed that EGR2 was highly expressed in bladder cancer tissues, and its overexpression was associated with poor prognosis. Knockdown of EGR2 inhibited bladder cancer cell proliferation, invasion, and migration. Conclusion: This study provides valuable insights into the landscape of SPRGS in bladder cancer and their potential implications for personalized treatment strategies. The identification of EGR2 as a key SPRG and its functional impact on bladder cancer cells further highlights its significance in bladder cancer development and progression. Overall, SPRGS may serve as important prognostic markers and predictive biomarkers for bladder cancer patients, guiding treatment decisions and improving patient outcomes.

Association study of the polymorphisms rs2228611 of the DNMT1 gene and rs1569686 of the DNMT3B gene with bladder cancer development in a sample of the Algerian population.

Bladder cancer (BC) is a multifactorial disease with a poorly understood main cause. In this study, we aimed to evaluate the effect of the polymorphisms rs2228611 of the DNMT1 gene and rs1569686 of the DNMT3B gene on the susceptibility to develop Bladder Cancer in the Algerian population. A case-control study design was adopted, with DNA samples of 114 BC patients and 123 healthy controls. We found that the rs2228611 of the DNMT1 gene was strongly associated with an increased risk of BC development under genetic models: Codominant AG vs. GG (OR=2.54, 95% CI=1.21-5.51, adj p=0.015) and dominant AA+AG vs. GG (OR=2.24, 95% CI=1.12-4.60, adj p=0.023). However, no statistically significant association was observed between the rs1569686 of the DNMT3B gene and the predisposition to BC. To the best of our knowledge, this is the first peer-reviewed study to evaluate the effect of the rs2228611 polymorphism on bladder cancer occurrence. Our results suggest that the rs2228611 might be a potential biomarker for BC development risk. Additional studies are needed to validate our findings.

Revealing the potential of solute carrier family 31 (copper transporters), member 1: Insights into its role in bladder cancer progression and therapeutic implications.

Introduction: Bladder cancer represents a significant public health concern with diverse genetic alterations influencing disease onset, progression, and therapy response. In this study, we explore the multifaceted role of Solute Carrier Family 31 Member 1 (SLC31A1) in bladder cancer, a pivotal gene involved in copper homeostasis. Methods: Our research involved analyzing the SLC31A1 gene expression via RT-qPCR, promoter methylation via targeted bisulfite sequencing, and mutational status via Next Generation Sequencing (NGS) using the clinical samples sourced by the local bladder cancer patients. Later on, The Cancer Genome Atlas (TCGA) datasets were utilized for validation purposes. Moreover, prognostic significance, gene enrichment terms, and therapeutic drugs of SLC31A1 were also explored using KM Plotter, DAVID, and DrugBank databases. Results: We observed that SLC31A1 was significantly up-regulated at both the mRNA and protein levels in bladder cancer tissue samples, suggesting its potential involvement in bladder cancer development and progression. Furthermore, our investigation into the methylation status revealed that SLC31A1 was significantly hypomethylated in bladder cancer tissues, which may contribute to its overexpression. The ROC analysis of the SLC31A1 gene indicated promising diagnostic potential, emphasizing its relevance in distinguishing bladder cancer patients from normal individuals. However, it is crucial to consider other factors such as cancer stage, metastasis, and recurrence for a more accurate evaluation in the clinical context. Interestingly, mutational analysis of SLC31A1 demonstrated only benign mutations, indicating their unknown role in the SLC31A1 disruption. In addition to its diagnostic value, high SLC31A1 expression was associated with poorer overall survival (OS) in bladder cancer patients, shedding light on its prognostic relevance. Gene enrichment analysis indicated that SLC31A1 could influence metabolic and copper-related processes, further underscoring its role in bladder cancer. Lastly, we explored the DrugBank database to identify potential therapeutic agents capable of reducing SLC31A1 expression. Our findings unveiled six important drugs with the potential to target SLC31A1 as a treatment strategy. Conclusion: Our comprehensive investigation highlights SLC31A1 as a promising biomarker for bladder cancer development, progression, and therapy.

Bladder Cancer Treatments in the Age of Personalized Medicine: A Comprehensive Review of Potential Radiosensitivity Biomarkers.

Bladder cancer is one of the most frequently diagnosed cancers in men. While cystectomy remains the primary treatment, advances in radiotherapy and chemotherapy have highlighted the value of bladder-preserving strategies, which can also enhance patients' quality of life. Despise these advances, around 20% of patients may still require salvage cystectomy due to tumor radioresistance. This underscores the need to develop radiosensitivity predictive assays. Radiotherapy acts by inducing DNA damage, primarily through DNA double-strand breaks, which can significantly affect treatment outcomes if left unrepaired. In addition to activating DNA repair pathways, the response to radiation also involves the tumor microenvironment, cell death pathways, immune responses and different types of cell death and proliferation receptors. In recent years, personalized medicine, which tailors treatments to individual patients, has gained increasing attention in cancer care. The development of chemo- and radiosensitivity predictive assays has become a key focus of cancer research. Despite the potential impact of such assays on bladder cancer treatment, there is still no reliable test that can help clinicians and informs patients in choosing the best treatment. This review aims to highlight studies that attempted to characterize bladder cancer radiosensitivity and to discuss the potential biomarkers that could be used to develop bladder cancer radiosensitivity predictive assays.

The alternation of halobenzoquinone disinfection byproduct on toxicogenomics of DNA damage and repair in uroepithelial cells

Halobenzoquinones (HBQs) were recently discovered as an emerging class of drinking water disinfection byproducts with carcinogenic concern. However, the molecular mechanism underlying HBQs-induced DNA damage is not clear. In this study, we integrated in vitro genotoxicity, computational toxicology, and the quantitative toxicogenomic analysis of HBQs on DNA damage/repair pathways in human bladder epithelial cells SV-HUC-1. The results showed that HBQs could induce cytotoxicity with the descending order as 2,6-DIBQ > 2,6-DCBQ ≈ 2,6-DBBQ. Also, HBQs can increase DNA damage in SV-HUC-1 cells and thus generate genotoxicity. However, there is no significant difference in genotoxicity among the three HBQs. The results of molecular docking and molecular dynamics simulation further confirmed that HBQs had high binding fractions and stability to DNA. Toxicogenomic analysis indicated that HBQs interfered with DNA repair pathways, mainly affecting base excision repair, nucleotide excision repair and homologous recombination repair. These results have provided new insights into the underlying molecular mechanisms of HBQs-induced DNA damage, and contributed to the understanding of the relationship between exposure to DBPs and risks of developing bladder cancer.

Early-stage diagnosis of bladder cancer using surface-enhanced Raman spectroscopy combined with machine learning algorithms in a rat model

Early diagnosis and accurate assessment of tumor development facilitate early bladder cancer resection and initiation of drug therapy. This study enabled an early, accurate, label-free, noninvasive diagnosis of bladder tumors by analyzing nano-biomarkers in a single drop of urine through surface-enhanced Raman spectroscopy (SERS). In a standard N-butyl-N-4-hydroxybutyl nitrosamine–induced rat model of bladder cancer, cancer stage and polyp tumor development were monitored using a small endoscope with a diameter of 1.2 mm in a minimally invasive manner without the need to kill the rats. Samples were divided into cancer-free, early-stage, and polyp-form cancer. Training data were classified according to micro-cystoscopic 5-aminolevulinic acid fluorescence diagnosis, and specimens were postmortem verified through histopathological analysis. A drop of urine from each sample group was placed on an Au-coated zinc oxide nanoporous chip to filter nano-biomaterials and selectively enhance the Raman signals of nanoscale analytes via SERS. Principal component analysis was used to reduce the dimensionality of the collected Raman spectra, and partial least squares discriminant analysis was used to find diagnostic clusters based on the labeled samples. The combination of SERS and machine learning achieved an accuracy ≥99.6% in diagnosing both early- and polyp-stage bladder tumors. With an area under the receiver operating characteristic curve greater than 0.996, the accuracy of the diagnosis in the rat model suggests that SERS-based diagnostic methods are promising when coupled with machine learning. Low-cost, label-free, and noninvasive surface-enhanced Raman spectra are ideal for developing clinically relevant point-of-care diagnostic techniques.