Overall Survival Of Bladder Cancer Patients Research Articles

Targeting the KAT8/YEATS4 Axis Represses Tumor Growth and Increases Cisplatin Sensitivity in Bladder Cancer.

Bladder cancer (BC) is one of the most common tumors characterized by a high rate of relapse and a lack of targeted therapy. Here, YEATS domain-containing protein 4 (YEATS4) is an essential gene for BC cell viability using CRISPR-Cas9 library screening is reported, and that HUWE1 is an E3 ligase responsible for YEATS4 ubiquitination and proteasomal degradation by the Protein Stability Regulators Screening Assay. KAT8-mediated acetylation of YEATS4 impaired its interaction with HUWE1 and consequently prevented its ubiquitination and degradation. The protein levels of YEATS4 and KAT8 are positively correlated and high levels of these two proteins are associated with poor overall survival in BC patients. Importantly, suppression of YEATS4 acetylation with the KAT8 inhibitor MG149 decreased YEATS4 acetylation, reduced cell viability, and sensitized BC cells to cisplatin treatment. The findings reveal a critical role of the KAT8/YEATS4 axis in both tumor growth and cisplatin sensitivity in BC cells, potentially generating a novel therapeutic strategy for BC patients.

Comprehensive analysis of mitochondria-related genes indicates that PPP2R2B is a novel biomarker and promotes the progression of bladder cancer via Wnt signaling pathway

Bladder cancer (BC) is the fourth and tenth most common malignancy in men and women worldwide, respectively. The complexity of the molecular biological mechanism behind BC is a major contributor to the lack of effective treatment management of the disease. The development and genesis of BC are influenced by mitochondrial retrograde control and mitochondria-nuclear cross-talk. However, the role of mitochondrial-related genes in BC remains unclear. In this study, we analyzed TCGA datasets and identified 752 DE-MRGs in BC samples, including 313 down-regulated MRGs and 439 up-regulated MRGs. Then, the results of machine-learning screened four critical diagnostic genes, including GLRX2, NMT1, PPP2R2B and TRAF3IP3. Moreover, we analyzed their prognostic value and confirmed that only PPP2R2B was associated with clinical prognosis of BC patients and Cox regression assays validated that PPP2R2B expression was a distinct predictor of overall survival in BC patients. Them, we performed RT-PCR and found that PPP2R2B expression was distinctly decreased in BC specimens and cell lines. Functional experiments revealed that overexpression of PPP2R2B distinctly suppressed the proliferation, migration and invasion of BC cells via Wnt signaling pathway. In summary, these research findings offer potential molecular markers for the diagnosis and prognosis of BC, with the discovery of PPP2R2B particularly holding significant biological and clinical significance. This study provides valuable clues for future in-depth investigations into the molecular mechanisms of BC, as well as the development of new diagnostic markers and therapeutic targets.

The value of ATAD3A as a potential biomarker for bladder cancer.

Bladder cancer (BCa) is a highly malignant tumor, and if left untreated, it can develop severe hematuria and tumor metastasis, thereby endangering the patient's life. The purpose of this paper was to detect the expression of ATAD3A in BCa and research the relationship between ATAD3A and pathological features of bladder cancer and the prognosis of patients. First, the expression of ATAD3A in BCa and normal bladder tissues was analyzed based on the UALCAN and Oncomine public databases. Second, 491 cases of surgically resected bladder cancer specimens and 110 cases of normal adjacent tissues were immunohistochemically stained. The expression of ATAD3A was quantified, and the value and prognosis of ATAD3A as a biomarker of BCa were evaluated. The expression of ATAD3A in bladder cancer tissues was higher than that in normal bladder mucosa. High expression of ATAD3A was correlated with patient age, tumor size, number of tumors, distant metastasis, lymph node metastasis, lymphovascular invasion, and TNM stage (p < 0.05). Overexpression of ATAD3A is closely related to cancer patient survival. The mean survival time of bladder cancer patients with high ATAD3A expression was shorter than those with low ATAD3A levels. According to the relative comparing result, the high ATAD3A expression herald reduced overall survival in BCa patients. The abnormal overexpression of ATAD3A may be related to the initiation and progress of bladder cancer. The upregulation of ATAD3A can be used as an effective indicator to diagnose bladder cancer and predict tumor progression. Furthermore, the combination of information from public databases and the results of clinical sample analysis can help us better understand the mechanism of action of molecular oncogenes in bladder cancer.

Comprehensive analysis of N1-methylandenosine regulators and m1A-related mRNAs and lncRNAs as prognostic factors in bladder cancer

Bladder cancer (BC) is a lethal malignancy and recurs frequently. m1A plays a vital role in maintaining the biological functions of non-coding RNAs. The Cancer Genome Atlas (TCGA) is a free website from where transcriptome data of BC were obtained. We chose m1A methylation regulators for this study. Six m1A methylation regulator genes have a higher expression in BC tissue compared to normal tissue. The aberrant expression of those m1A regulator genes was remarkably related to BC prognosis and clinicopathological features. First, m1A-related mRNAs and long noncoding RNAs (lncRNAs) were identified. Next, univariate Cox regression, least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression were performed to get the optimum RNAs for the development of prognostic signatures. Also, a nomogram with T status, lncRNA risk scores and mRNA risk scores was constructed. It revealed an adequate capacity to predict the overall survival of BC cases in the training set as well as in the testing set and in the total TCGA cohort. In conclusion, m1A methylation regulator genes played an important role in predicting the overall survival of BC patients. In addition, m1A-related lncRNAs and mRNAs illustrated underlying mechanisms of tumorigenesis and development of BC.

Novel potential urinary biomarkers for effective diagnosis and prognostic evaluation of high-grade bladder cancer.

High-grade bladder cancer (HGBC) has a higher malignant potential, recurrence and progression rate compared to low-grade phenotype. Its early symptoms are often vague, making non-invasive diagnosis using urinary biomarkers a promising approach. The gene expression data from urine samples of patients with HGBC was extracted from the GSE68020 dataset. The clinical information and gene expression data in tumor tissues of HGBC patients were obtained from The Cancer Genome Atlas (TCGA) database. Multivariate Cox analysis was used to predict the optimal risk model. The protein-protein interaction (PPI) analysis was performed via the Search Tool for the Retrieval of Interacting Genes (STRING) database and visualized using Cytoscape. Overall survival (OS) was evaluated in the Gene Expression Profiling Interactive Analysis (GEPIA) online platform. Competing endogenous RNA (ceRNA) network was also visualized using Cytoscape. The expression levels of specific genes were assessed through quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Moreover, co-expressed genes and potential biological functions related to specific genes were explored based on the Cancer Cell Line Encyclopedia (CCLE) database. A total of 560 differentially expressed genes (DEGs) were identified when comparing the urine sediment samples from HGBC patients with the benign ones. Using these urinary DEGs and the clinical information of HGBC patients, we developed an optimal risk model consisting of eight genes to predict the patient outcome. By integrating the node degree values in the PPI network with the expression changes in both urine and tissue samples, eighteen hub genes were selected out. Among them, DKC1 and SNRPG had the most prominent comprehensive values, and EFTUD2, LOR and EBNA1BP2 were relevant to a worse OS in bladder cancer patients. The ceRNA network of hub genes indicated that DKC1 may be directly regulated by miR-150 in HGBC. The upregulation of both SNRPG and DKC1 were detected in HGBC cells, which were also observed in various tumor tissues and malignant cell lines, displaying high correlations with other hub genes. Our study may provide theoretical basis for the development of effective non-invasive detection and treatment strategies, and further research is necessary to explore the clinical applications of these findings.

LDL receptor related protein 1 is an adverse prognostic biomarker that correlates with stromal remodeling and macrophages infiltration in bladder cancer.

Bladder cancer (BLCA) is a highly heterogeneous disease influenced by the tumor microenvironment, which may affect patients' response to immune checkpoint blockade therapy. Therefore, identifying molecular markers and therapeutic targets to improve treatment is essential. In this study, we aimed to investigate the prognostic significance of LRP1 in BLCA. We analyzed TCGA and IMvigor210 cohorts to investigate the relationship of LRP1 with BLCA prognosis. We utilized gene mutation analysis and enrichment to identify LRP1-associated mutated genes and biological processes. Deconvolution algorithms and single-cell analysis were used to understand the tumor-infiltrated cells and biological pathways associated with LRP1 expression. Immunohistochemistry was conducted to validate the bioinformatics analysis. Our study revealed that LRP1 was an independent risk factor for overall survival in BLCA patients and was associated with clinicopathological features and FGFR3 mutation frequency. Enrichment analysis demonstrated that LRP1 was involved in extracellular matrix remodeling and tumor metabolic processes. Furthermore, the ssGSEA algorithm revealed that LRP1 was positively correlated with the activities of tumor-associated pathways. Our study also found that high LRP1 expression impaired patients' responsiveness to ICB therapy in BLCA, which was predicted by TIDE prediction and validated by IMvigor210 cohort. Immunohistochemistry confirmed the expression of LRP1 in Cancer-Associated Fibroblasts (CAFs) and macrophages in the tumor microenvironment of BLCA. Our study suggests that LRP1 may be a potential prognostic biomarker and therapeutic target in BLCA. Further research on LRP1 may improve BLCA precision medicine and enhance the efficacy of immune checkpoint blockade therapy.

Prediction of immune infiltration and prognosis for patients with urothelial bladder cancer based on the DNA damage repair-related genes signature

ObjectivesTo analyze the correlations between the expression and effect of DNA damage repair genes and the immune status and clinical outcomes of urothelial bladder cancer (BLCA) patients. In addition, we evaluate the efficacy and value of utilizing the DNA damage repair genes signature as a prognosis model for BLCA. MethodsTwo subtype groups (C1 and C2) were produced based on the varied expression of DNA damage repair genes. Significantly differentiated genes and predicted enriched gene pathways were obtained between the two subtypes. Seven key genes were obtained from the DNA damage repair-related genes and a 7-gene signature prognosis model was established based on the key genes. The efficacy and accuracy of this model in prognosis prediction was evaluated and verified in two independent databases. Also, the difference in biological functions, drug sensitivity, immune infiltration and affinity between the high-risk group and low-risk group was analyzed. ResultsThe DNA damage repair gene signature could significantly differentiate the BLCA into two molecular subgroups with varied genetic expression and enriched gene pathways. Seven key genes were screened out from the 232 candidate genes for prognosis prediction and a 7-gene signature prognosis model was established based on them. Two independent patient cohorts (TCGA cohort and GEO cohort) were utilized to validate the efficacy of the prognosis model, which demonstrated an effective capability to differentiate and predict the overall survival of BLCA patients. Also, the high-risk group and low-risk group derived from the 7-gene model exhibited significantly differences in drug sensitivity, immune infiltration status and biological pathways enrichment. ConclusionsOur established 7-gene signature model based on the DNA damage repair genes could serve as a novel prognosis predictive tool for BLCA. The differentiation of BLCA patients based on the 7-gene signature model may be of great value for the appropriate selection of specific chemotherapy agents and immune-checkpoint blockade therapy administration.

Sarcopenia is an independent predictor of survival in patients undergoing radical cystectomy for bladder cancer: a single-centre, retrospective study.

This study aimed to determine whether sarcopenia is a predictor of overall survival (OS) and cancer-specific survival (CSS) in patients with bladder cancer (BC) undergoing radical cystectomy (RC). Patients who underwent radical cystectomy for BC between September 2016 and June 2022 were retrospectively reviewed. Patients underwent digital computed tomography (CT) scans of the abdomen and pelvis. The skeletal muscle index (SMI) was used to assess sarcopenia using CT images. OS and CSS were estimated using Kaplan-Meier curves. Predictors of CSS and OS were analysed using univariate and multivariate Cox regression models. Of the 84 reviewed patients, 45 (53.6%) had sarcopenia. The median follow-up period for survivors was 70 months. Patients with sarcopenia were older and had a lower BMI, but other preoperative clinical and laboratory parameters were similar to those of patients without sarcopenia. During follow-up, 57 (67.9%) patients died, 39 (46.4%) due to BC. In addition, patients with sarcopenia had worse 5-year OS (24.4% vs 41.0%, p = 0.036) and CSS (35.6% vs 61.5%, p = 0.012) than non-sarcopenic patients. The findings indicate that sarcopenia is an independent predictor of increased CSS (HR, 2.841; p = 0.003) and overall mortality (HR, 2.465; p = 0.004) in multivariate analysis. The results of this study support the view that sarcopenia is an important risk factor for predicting CSS and OS in BC patients undergoing RC.

Starvation-induced long non-coding RNAs are significant for prognosis evaluation of bladder cancer.

Starving intratumoral microenvironment prominently alters genic profiles including long non-coding RNAs (lncRNAs), which further regulate bladder cancer (BCa) malignant biological properties, such as invasion and migration. Transcriptome RNA-sequencing data of 414 BCa tumor tissues and 19 normal tissues were obtained from TCGA database and paired samples of 132 BCa patients. A chain of in vitro validations such as qPCR, migration and invasion assays were performed to reveal the clinical relevance of AC011472.4 and AL157895.1. A total of 11 lncRNAs were identified as starvation-related lncRNAs, of which AC011472.4 and AL157895.1 were relevant to overall survival of BCa patients. Besides, a starvation-related risk score model was established based on the levels of AC011472.4 and AL157895.1. BCa patients with higher levels of AL157895.1 were divided into the high-risk group and usually obtained higher mortality rate, but AC011472.4 was contrary. AL157895.1 expressed highly in BCa cell lines and tumour tissues, especially in patients with the advanced grade, stage and T-stage, while AC011472.4 showed the reversed result. Moreover, increased level of AL157895.1 was remarkably correlated to T-stage, muscle invasion status and distant metastasis. SiRNAs-mediated silence of AC011472.4 and AL157895.1 respectively increased and diminished invasion and migration properties of BCa cells. In this study, we highlight the significant roles of AC011472.4 and AL157895.1 on evaluating prognoses of BCa patients and validate their correlation with various clinical parameters. These findings provide an appropriate risk score model for BCa clinical decision making.

PLK1 as one novel target for the poor prognosis of bladder cancer: An observational study.

Bladder cancer (BC) is one of the most common male malignant tumors and the most common urological tumor. However, the molecular mechanism and role of PLK1 on bladder cancer were unclear. Therefore, the study aims to explore the potential part of the overall survival of bladder cancer through bioinformatics analysis. GSE121711 and GSE130598, from the Gene Expression Omnibus database. The GEO2R screened differently expressed genes, and DAVID and Metascape were used for functional annotation. The cytoHubba made hub genes identification and expression. A total of 50 BC participants were recruited. After surgery, 50 BC tumor samples from BC patients and 50 adjacent standard bladder tissue samples were obtained. The RT-qPCR assay was performed to verify the expression of hub genes. The Kaplan–Meier Plotter analyzed the effect of hub gene expression for overall survival of BC. The compulsory module of Molecular Complex Detection tool analysis was shown, which included CDK1, TTK, AURKB, MELK, PLK1, and BUB1. And the six hub genes were up-regulated in the BC compared with the normal tissues. The relative expression levels of CDK1, TTK, AURKB, MELK, PLK1, and BUB1 were significantly higher in BC samples compared with the regular kidney tissue groups. The result demonstrated that CDK1, TTK, AURKB, MELK, PLK1, and BUB1 might be considered biomarkers for BC. Overall survival analysis showed that BC patients with high expression level of PLK1 had poorer overall survival times than those with low expression level (P < .05). The expression levels of CDK1, TTK, AURKB, MELK, and BUB1 was not related to the overall survival of BC patients (P > .05). The PLK1 gene might provide new ideas and evidence for bladder cancer research.

HYAL3 as a potential novel marker of BLCA patient prognosis

BackgroundIt has been previously demonstrated that hyaluronan (HA) potentially regulates the initiation and propagation of bladder cancer (BLCA). HYAL3 encodes hyaluronidase and is a potential therapeutic target for BLCA. We aimed to explore the role that HYAL3 plays in BLCA pathogenesis.MethodsHYAL3 expression in BLCA specimens was analyzed using The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) cohort as well as confirmed in cell lines and The Human Protein Atlas. Then, associations between HYAL3 expression and clinicopathological data were analyzed using survival curves and receiver-operating characteristic (ROC) curves. The functions of HYAL3 were further dissected using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and the protein–protein interaction network. Finally, we harnessed the Tumor IMmune Estimation Resource and Gene Expression Profiling Interactive Analysis to obtain correlations between HYAL3 expression, infiltrating immunocytes, and the corresponding immune marker sets.ResultsHYAL3 expression varied greatly between many types of cancers. In addition, a higher HYAL3 expression level predicted a poor overall survival (OS) in both TCGA-BLCA and GEO gene chips (P < 0.05). HYAL3 also exhibited an acceptable diagnostic ability for the pathological stage of BLCA (area under the receiver-operating characteristic curve = 0.769). Furthermore, HYAL3 acted as an independent prognostic factor in BLCA patients and correlated with the infiltration of various types of immunocytes, including B cells, CD8+ T cells, cytotoxic cells, T follicular helper cells, and T helper (Th) 2 cells.ConclusionHYAL3 might serve as a potential biomarker for predicting poor OS in BLCA patients and correlated with immunocyte infiltration in BLCA.

Comprehensive Characterization of Necroptosis-Related lncRNAs in Bladder Cancer Identifies a Novel Signature for Prognosis Prediction.

Background Bladder cancer (BC) is one of the most serious genitourinary malignant diseases with a poor prognosis. Necroptosis is a regulated form of cell death, and targeting necroptosis is emerging as a potential tumor therapy strategy. Nevertheless, the roles of necroptosis-related long noncoding RNAs (nrlncRNAs) in BC remains to be illustrated. This work is aimed at studying the clinical implications of nrlncRNAs in BC. Methods The RNA-seq data and corresponding clinical data, downloaded from The Cancer Genome Atlas (TCGA) database, were utilized to obtain prognostic nrlncRNAs and construct a prediction nomogram for BC. The comprehensive profiling of the functional pathways, immune status, mutational landscape, and drug sensitivity related to the necroptosis-related lncRNA signature (NerRLsig) was performed. Results Herein, a signature consisting of 12 necroptosis-related lncRNAs (AC015802.4, AL391807.1, AL078644.1, AC023825.2, AL132655.2, AP003352.1, STAG3L5P-PVRIG2P-PILRB, AC024451.4, MAP3K14-AS1, AL731567.1, AC010542.5, and AC009299.2) was constructed. The established signature can independently predict the poor overall survival of BC patients. Additionally, the NerRLsig had higher diagnostic validity compared to other clinicopathological variables, with a greater area under the receptor operating characteristic and concordance index curves. Finally, we found the differences in the functional signaling pathway, immune status, mutational profile, and drug sensitivity between the two subgroups. Conclusion This research revealed that the prognostic NerRLsig and nomogram could accurately predict the prognosis of BC.

Preoperative Metabolic Syndrome and HDL-C Level Predict the Prognosis of Patients Following Radical Cystectomy: A Propensity Score Matching Study.

ObjectiveTo investigate the prognostic significance of metabolic syndrome (MetS) and its components in patients with bladder cancer (BCa) treated with radical cystectomy (RC).MethodsA total of 335 BCa patients who underwent RC between 2004 and 2019 at Peking University Third Hospital (PUTH) were analyzed retrospectively. The Kaplan-Meier method with the log-rank test was performed to assess overall survival (OS) and progression-free survival (PFS). Univariate and multivariate Cox proportional hazard models were conducted to identify the prognostic factors of OS and PFS before and after propensity score matching (PSM).ResultsEnrolled patients were allocated into two groups according to the presence or absence of MetS (n=84 MetS vs n=251 non-MetS), and 82 new matched pairs were identified to balance the baseline characteristics after 1:1 PSM. In the Kaplan-Meier analysis, MetS was associated with better OS (P=0.031) than the group without MetS. In addition, a body mass index (BMI) ≥ 25 was associated with better OS (P=0.011) and PFS (P=0.031), while low high-density lipoprotein cholesterol (HDL-C) was associated with worse OS (P=0.033) and PFS (P=0.010). In all patients, multivariate Cox analysis showed that hemoglobin, pathologic tumor stage and lymph node status were identified as independent prognostic factors for both OS and PFS, while age, MetS and HDL-C were independent prognostic factors only for OS. Reproducible results of multivariate analysis can still be observed in propensity matched patients. The results of further subgroup analysis revealed that the association of MetS with increased OS (P=0.043) and BMI ≥25 with increased OS (P=0.015) and PFS (P=0.029) was observed in non-muscle invasive bladder cancer (NMIBC) patients.ConclusionsMetS was independently associated with better OS in BCa patients after RC, and HDL-C was the only component of MetS that was independently associated with worse OS. MetS and HDL-C may become reliable prognostic biomarkers of OS in BCa patients after RC to provide individualized prognostication and assist in the formulation of clinical treatment strategies.

Circ3323 Motivates Host Gene to Promote the Aggressiveness of Bladder Cancer.

Bladder cancer (BCa) is the most common cancer in the urinary system with high recurrence rate and poor prognosis. Circular RNA (circRNA) is a novel subclass of noncoding-RNA which participate in progression of BCa. Here, we identified a novel circRNA-circ3323 and aimed to investigate the role of circ3323 in progression of BCa. Public data of RNA sequencing was used to identify significant circRNA related to BCa. The role of circRNAs in progression of BCa was assessed in cytotoxicity assay, transwell assay and flow cytometry. Biotin-coupled RNA pull-down and fluorescence in situ hybridization were performed to evaluate the interaction between circRNAs and miRNAs. The expression of circ3323 was higher in BCa tissues and cells than in normal samples. Experiments in vitro showed that the knockdown of circ3323 inhibited cell proliferation and impeded the metastasis of BCa cells. Mechanistically, we demonstrated that circ3323 acts as a sponge for miR-186-5p and promotes host gene APP's expression. Clinically, circ3323 predicts worse overall survival of BCa patients, indicating its prognostic value. Our study identified that circ3323 modulates metastasis of BCa through miR-186-5p/APP axis and may serve as a promising prognostic biomarker for BCa, which provides novel insights into treatment of BCa.

Integrative Analysis Identified MCT4 as an Independent Prognostic Factor for Bladder Cancer.

BackgroundBladder cancer is the 10th most common cancer and most common urothelial malignancy worldwide. Prognostic biomarkers for bladder cancer patients are required for individualized treatment. Monocarboxylate transporter 4 (MCT4), encoded by SLC16A3 gene, is a potential biomarker for bladder cancer because of its crucial role in the lactate efflux in the aerobic glycolysis process. We aimed to study the association between MCT4 expression and the overall survival (OS) of bladder cancer patients.MethodsThe published single-cell RNA sequencing data of 49,869 bladder cancer cells and 15,827 normal bladder mucosa cells and The Cancer Genome Atlas (TCGA) bladder cancer cohort data were used to explore the mRNA expression of SLC16A3 in bladder cancer. Eighty-nine consecutive bladder cancer patients who had undergone radical cystectomy were enrolled as a validation cohort. The expression of MCT4 proteins in bladder cancer specimens was detected using immunohistochemistry staining. The Kaplan–Meier survival analysis and Cox regression were performed to analyze the association between MCT4 protein expression and OS in bladder cancer patients.ResultsSLC16A3 mRNA was upregulated in bladder cancer cells. The upregulated genes in SLC16A3-positive epithelial cells were enriched in the glycolysis process pathway and monocarboxylic acid metabolic process pathway. Patients with high SLC16A3 mRNA expression showed significantly poor OS (p = 0.016). High MCT4 protein expression was also found to be an independent predictor for poor OS in bladder cancer patients (HR: 2.462; 95% CI: 1.202~5.042, p = 0.014). A nomogram was built based on the results of the multivariate Cox analysis.ConclusionBladder cancer with high SLC16A3 mRNA expression has a poor OS. High MCT4 protein expression is an independent prognostic factor for bladder cancer patients who had undergone radical cystectomy.

An immune cell infiltration-related gene signature predicts prognosis for bladder cancer

To explore novel therapeutic targets, develop a gene signature and construct a prognostic nomogram of bladder cancer (BCa). Transcriptome data and clinical traits of BCa were downloaded from UCSC Xena database and Gene Expression Omnibus (GEO) database. We then used the method of Single sample Gene Set Enrichment analysis (ssGSEA) to calculate the infiltration abundances of 24 immune cells in eligible BCa samples. By weighted correlation network analysis (WGCNA), we identified turquoise module with strong and significant association with the infiltration abundance of immune cells which were associated with overall survival of BCa patients. Subsequently, we developed an immune cell infiltration-related gene signature based on the module genes (MGs) and immune-related genes (IRGs) from the Immunology Database and Analysis Portal (ImmPort). Then, we tested the prognostic power and performance of the signature in both discovery and external validation datasets. A nomogram integrated with signature and clinical features were ultimately constructed and tested. Five prognostic immune cell infiltration-related module genes (PIRMGs), namely FPR1, CIITA, KLRC1, TNFRSF6B, and WFIKKN1, were identified and used for gene signature development. And the signature showed independent and stable prognosis predictive power. Ultimately, a nomogram consisting of signature, age and tumor stage was constructed, and it showed good and stable predictive ability on prognosis. Our prognostic signature and nomogram provided prognostic indicators and potential immunotherapeutic targets for BCa. Further researches are needed to verify the clinical effectiveness of this nomogram and these biomarkers.

Identification of Lymph Node Metastasis-Related Key Genes and Prognostic Risk Model in Bladder Cancer by Co-Expression Analysis.

Background: Lymph node metastasis (LNM) is an important pathological characteristic of bladder cancer (BCa). However, the molecular mechanism underlying LNM was not thoroughly elaborated. Identification for LNM-related biomarkers may contribute to making suitable therapies. So, the current study was aimed to identify key genes and construct a prognostic signature. Methods: Based on the Cancer Genome Atlas (TCGA) database, gene expression and clinical information were obtained. Then, the weighted gene co-expression network analysis (WGCNA) was performed to identify the key modules and hub genes. A function analysis and a gene set enrichment analysis were applied to explore biological functions and pathways of interested genes. Furthermore, a prognostic model based on LNM-related genes was constructed by using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Results: Finally, nine co-expression modules were constructed, and two modules (turquoise and green) were significantly associated with LNM. Three hub genes were identified as DACT3, TNS1, and MSRB3, which were annotated in actin binding, actin cytoskeleton, adaptive immune response, and cell adhesion molecular binding by the GSEA method. Further analysis demonstrated that three hub genes were associated with the overall survival of BCa patients. In addition, we built a prognostic signature based on the genes from LNM-related modules and evaluated the prognostic value of this signature. Conclusion: In general, this study revealed the key genes related to LNM and prognostic signature, which might provide new insights into therapeutic target of BCa.

Long Noncoding RNA LINC00707 Accelerates Tumorigenesis and Progression of Bladder Cancer via Targeting miR-145/CDCA3 Regulatory Loop

Introduction: Growing studies reveal that long noncoding RNA is involved in oncogenesis and progression. Previous studies have demonstrated that long intergenic noncoding RNA 00707 (LINC00707) stimulated tumor progress in numerous neoplasm types; however, the function of LINC00707 in bladder cancer (BC) was not yet clear. Our researches aimed to determine whether LINC00707 was dysregulated in BC and further study its biological functions. Methods: LINC00707 levels in BC tissues and cells were measured using reverse transcription-PCR (RT-PCR), and the associations between the levels of LINC00707 and clinicopathological features and the months of survival were also examined. Then, Cell Counting Kit-8 assays, flow cytometry, colony formation assays, and Transwell assays were applied for the assessment of the impact of LINC00707 on the abilities of BC cells. The interaction between LINC00707 and miR-145 or cell division cycle associated 3 was determined by luciferase reporter system and RT-PCR. Protein expressions of Wnt/β-catenin signaling were examined using RT-PCR and Western blot. Results: We found that LINC00707 expressions were notably upregulated in BC samples and cells. Higher expressions of LINC00707 were associated with T stage, grade, and shorter overall survival in BC patients. LINC00707 was also an independent prognostic factor for BC. In vitro assays confirmed that silencing LINC00707 expressions suppressed cell proliferation, colony formation, and metastasis. Mechanistic studies elucidated that LINC00707 was directly targeted to miR-145/CDCA3. Western blot assays revealed that Wnt/β-catenin signaling was inactivated by LINC00707 knockdown. Conclusion: Our work offers new insight into the function of LINC00707 in the tumorigenesis of BC.

A Novel Nomogram Based on Machine Learning-Pathomics Signature and Neutrophil to Lymphocyte Ratio for Survival Prediction of Bladder Cancer Patients.

Traditional histopathology performed by pathologists through naked eyes is insufficient for accurate survival prediction of bladder cancer (BCa). In addition, how neutrophil to lymphocyte ratio (NLR) could be used for prognosis prediction of BCa patients has not been fully understood. In this study, we collected 508 whole slide images (WSIs) of hematoxylin–eosin strained BCa slices and NLR value from the Shanghai General Hospital and The Cancer Genome Atlas (TCGA), which were further processed for nuclear segmentation. Cross-verified prediction models for predicting clinical prognosis were constructed based on machine learning methods. Six WSIs features were selected for the construction of pathomics-based prognosis model, which could automatically distinguish BCa patients with worse survival outcomes, with hazard ratio value of 2.19 in TCGA cohort (95% confidence interval: 1.63–2.94, p <0.0001) and 3.20 in General cohort (95% confidence interval: 1.75–5.87, p = 0.0014). Patients in TCGA cohort with high NLR exhibited significantly worse clinical survival outcome when compared with patients with low NLR (HR = 2.06, 95% CI: 1.29–3.27, p <0.0001). External validation in General cohort also revealed significantly poor prognosis in BCa patients with high NLR (HR = 3.69, 95% CI: 1.83–7.44 p <0.0001). Univariate and multivariate cox regression analysis proved that both the MLPS and the NLR could act as independent prognostic factor for overall survival of BCa patients. Finally, a novel nomogram based on MLPS and NLR was constructed to improve their clinical practicability, which had excellent agreement with actual observation in 1-, 3- and 5-year overall survival prediction. Decision curve analyses both in the TCGA cohort and General cohort revealed that the novel nomogram acted better than both the tumor grade system in prognosis prediction. Our novel nomogram based on MLPS and NLR could act as an excellent survival predictor and provide a scalable and cost-effective method for clinicians to facilitate individualized therapy. Nevertheless, prospective studies are still needed for further verifications.

Prognostic value of members of NFAT family for pan-cancer and a prediction model based on NFAT2 in bladder cancer.

Bladder cancer (BLCA) is one of the common malignant tumors of the urinary system. The poor prognosis of BLCA patients is due to the lack of early diagnosis and disease recurrence after treatment. Increasing evidence suggests that gene products of the nuclear factor of activated T-cells (NFAT) family are involved in BLCA progression and subsequent interaction(s) with immune surveillance. In this study, we carried out a pan-cancer analysis of the NFAT family and found that NFAT2 is an independent prognostic factor for BLCA. We then screened for differentially expressed genes (DEGs) and further analyzed such candidate gene loci using gene ontology enrichment to curate the KEGG database. We then used Lasso and multivariate Cox regression to identify 4 gene loci (FER1L4, RNF128, EPHB6, and FN1) which were screened together with NFAT2 to construct a prognostic model based on using Kaplan-Meier analysis to predict the overall survival of BLCA patients. Moreover, the accuracy of our proposed model is supported by deposited datasets in the Gene Expression Omnibus (GEO) database. Finally, a nomogram of this prognosis model for BLCA was established which could help to provide better disease management and treatment.