Prognosis Of Bladder Cancer Patients Research Articles

M6A-Related lncRNA to Develop Prognostic Signature and Predict the Immune Landscape in Bladder Cancer.

Abnormal m6A methylation plays a significant role in cancer progression. Increasingly, researchers have focused on developing lncRNA signatures to evaluate the prognosis of cancer patients. The specific function of m6A-related lncRNAs in the prognosis of bladder cancer patients and the immune microenvironment of bladder cancer remains elusive. Herein, we performed a comprehensive analysis of m6A-related lncRNA prognostic values and their association with the immune microenvironment in bladder cancer using the TCGA dataset. A total of 9 m6A-related lncRNAs were dramatically correlated with overall survival outcomes in bladder cancer. Two molecular subtypes (cluster 1 and cluster 2) were identified by consensus clustering for 9 m6A-related prognostic lncRNAs. Cluster 1 was significantly correlated with poor prognosis, advanced clinical stage, higher PD-L1 expression, a higher ESTIMATEScore and immuneScore, and distinct immune cell infiltration. GSEA revealed the enrichment of apoptosis and the JAK-STAT signaling pathway in cluster 2. A prognostic risk score was constructed using 9 m6A-related prognostic lncRNAs, which functioned as an independent prognostic factor for bladder cancer. Moreover, bladder cancer patients in the low-risk score group had a higher pN stage, pT stage, and clinical stage and a lower tumor grade and immuneScore. The risk score was correlated with the infiltration levels of certain immune cells, including B cells, plasma cells, follicular helper T cells, regulatory T cells, resting NK cells, neutrophils, M0 macrophages, M1 macrophages, and M2 macrophages. Collectively, our study elucidated the important role of m6A-related lncRNAs in the prognosis of bladder cancer patients and in the bladder cancer immune microenvironment. The results suggest that the components of the m6A-related prognostic lncRNA signature might serve as a crucial mediator of the immune microenvironment in bladder cancer, representing promising therapeutic targets for improving immunotherapeutic efficacy.

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.

PLD1 promotes tumor invasion by regulation of MMP-13 expression via NF-κB signaling in bladder cancer

Invasion of bladder cancer (BC) cells from the mucosa into the muscle layer is canonical for BC progression while phospholipase D isoform 1 (PLD1) is known to mediate development of cancer through phosphatidic acid (PA) production. We therefore used in silico, in vitro and in vivo approaches to detail the effect of PLD1 on BC invasion. In BC patients, higher levels of PLD1 expression were associated with poor prognoses. PLD1 knockdown significantly suppressed cellular invasion by human BC cells and matrix metalloproteinase-13 (MMP-13) was observed to mediate this effect. In our mouse bladder carcinogenesis model, the development of invasive BCs was suppressed by PLD1 knockout and a global transcriptomic analysis in this model indicated MMP-13 as a potential tumor invasion gene with NF-κB (nuclear factor-kB) as its transcriptional regulator. Furthermore, PA administration increased MMP-13 expression in line with NF-κB p65 phosphorylation levels. Collectively, we demonstrate that PLD1 promotes tumor invasion of BC by regulation of MMP-13 expression through the NF-κB signaling pathway and that PLD1 might be a potential therapeutic target to prevent clinical progression in BC patients.

RBM24 exacerbates bladder cancer progression by forming a Runx1t1/TCF4/miR-625-5p feedback loop

RNA–binding motif protein 24 (RBM24) acts as a multifunctional determinant of cell fate, proliferation, apoptosis, and differentiation during development by regulating premRNA splicing and mRNA stability. It is also implicated in carcinogenesis, but the functions of RBM24 in bladder cancer (BC) remain unclear. In the present study, we revealed that RBM24 was upregulated in BC tissues. Importantly, we found that a higher level of RBM24 was correlated with poor prognosis in BC patients. Overexpression of RBM24 promoted BC cell proliferation, while depletion of RBM24 inhibited BC cell proliferation in vivo and in vitro. Mechanistically, RBM24 positively regulated Runx1t1 expression in BC cells by binding to and enhancing Runx1t1 mRNA stability. Furthermore, Runx1t1 in turn promoted RBM24 expression by interacting with the transcription factor TCF4 and suppressing the transcription of miR-625-5p, which directly targets RBM24 and suppresses RBM24 expression. RBM24-regulated BC cell proliferation was moderated via the Runx1t1/TCF4/miR-625-5p feedback loop. These results indicate that the RBM24/Runx1t1/TCF4/miR-625-5p positive feedback loop participates in BC progression. Disruption of this pathway may be a potential therapeutic strategy for BC treatment.

Loss of polarity protein Par3, via transcription factor Snail, promotes bladder cancer metastasis.

Bladder cancer (BLCA) remains the leading cause of cancer‐related mortality among genitourinary malignancies worldwide. BLCA metastasis represents the primary reason for its poor prognosis. In this study, we report that decreased expression of partitioning defective 3 (Par3), a polarity protein (encoded by PARD3), is associated with tumor aggressive phenotypes and poor prognosis in BLCA patients. Consistently, ablation of Par3 promotes the metastasis and invasion of BLCA cells in vitro and in vivo. Further studies reveal that zinc finger protein Snail represses the expression of Par3 by binding to E2‐box (CAGGTG) of PARD3 promoter‐proximal. Inhibition of GSK‐3β promotes the expression and nuclear localization of Snail and then reduces the expression of Par3, resulting in the metastasis and invasion of BLCA cells. Moreover, we detected the interaction between Par3 (936‐1356 aa) and ZO‐1 (1372‐1748 aa), which is involved in the maintenance of tight junction. Together, our results demonstrate that the GSK‐3β/Snail/Par3/ZO‐1 axis regulates BLCA metastasis, and Snail is a major regulator for Par3 protein expression in BLCA.

Association Between the Pretreatment Albumin-to-Alkaline Phosphatase Ratio and Clinical Outcomes in Patients With Bladder Cancer Treated With Radical Cystectomy: A Retrospective Cohort Study.

ObjectiveSerum albumin-to-alkaline phosphatase ratio (AAPR) has been proven to be a prognostic indicator of many malignant tumors. However, whether it can predict the prognosis of bladder cancer (BC) patients who underwent radical cystectomy (RC) remains unclear. This study was designed to assess the relationship between AAPR and clinical outcomes in patients with BC treated with RC.MethodsThe clinicopathological data of 199 BC patients receiving RC in our institution from January 2012 to December 2017 were retrospectively collected and analyzed. They were divided into three groups based on the optimal cut-off values and the association between AAPR groups and their clinical outcomes were evaluated.ResultsThe average age of the patients was (64.0 ± 8.7) years and 79.9% were male. Based on the cut-off values of AAPR, patients were divided into three groups: low-AAPR group (AAPR < 0.37, n = 35), medium-AAPR group (AAPR = 0.37-0.59, n = 61) and high-AAPR group (AAPR > 0.59, n = 103). The median overall survival (OS) of each AAPR group was 12.5, 24, and 29 months, respectively (P value <0.0001). After adjusting the Cox proportional hazards model, medium- and high- AAPR groups showed a reduced risk trend of death, with a risk ratio of 0.44 (95% CI = 0.21-0.91) and 0.25 (95% CI = 0.12-0.49), respectively (P for trend <0.001). No nonlinear relationship was identified by smooth fitting curve between AAPR and OS. By subgroup analysis, we observed that compared to the low-AAPR group, the trends of the HRs in the medium- and high-AAPR group were decreased across nearly all subgroups after stratification. Moreover, the AAPR-based nomograms for OS, CSS and RFS were also constructed. The C-index showed a good predictive accuracy (OS, C-index 0.728, 95% CI 0.663-0.793; CSS, C-index 0.792, 95% CI 0.748-0.838; RFS, C-index 0.784, 95% CI 0.739-0.829).ConclusionPretreatment AAPR is significantly associated with the prognosis of BC patients receiving RC, which can be conducive to the clinical decision-making and risk stratification in those patients. The nomogram based on AAPR is a reliable model for predicting survival of BC patients after RC.

Circ-ZFR Promotes Progression of Bladder Cancer by Upregulating WNT5A Via Sponging miR-545 and miR-1270.

BackgroundBladder cancer is one of the most common cancers all over the world. CircZFR is a circular RNA and has been implicated in tumor generation and invasion. However, the exact role of circZFR in the development of bladder cancer (BCa) remains unknown. This study aimed to investigate the function of circZFR in BCa, and further to probe into the association between circ-ZFR, miR-545/miR-1270 and WNT5A.MethodsThe expression of circZFR in BCa was quantified by qRT-PCR and was positively correlated with the prognosis of BCa patients. Next, the stable knockdown of circZFR BCa cell lines was established and the resulting capacities of proliferation, migration and invasion were measured. The association of circZFR with miR-1270/miR-545 was predicted by circinteractome prediction, and was confirmed by luciferase assay as well as RNA pull down assay. Furthermore, miRNA inhibitors, WNT5A overexpression and Pearson correlation analysis were used to examine the relationship between circZFR, miR-1270/miR-545 and WNT5A.ResultsThe expression of CircZFR was up-regulated both in BCa tissues and in BCa cell lines, and was positively correlated with patient survival rates. Blocking of circZFR’s expression by RNA inhibitors suppressed the proliferation, migration and invasion of BCa cells both in vitro and in vivo. On the other hand, overexpression of target miRNA supported that circZFR directly interact with miR-545 and miR-1270. Moreover, we demonstrated that circZFR promotes the progression of BCa by upregulating WNT5A’s expression via sponging miR-545 and miR-1270.ConclusionsCircZFR promotes the proliferation, migration and invasion of BCa cells by upregulating WNT5A signaling pathway via sponging miR-545 and miR-1270. These results provide new insights into the molecular mechanism of circZFR in BCa progression, and more important, a novel target for BCa clinical treatment.

Comprehensive analysis of the lncRNA-miRNA-mRNA regulatory network for bladder cancer.

BackgroundLong non-coding RNAs (lncRNAs) are essential regulators for various human cancers. However, these lncRNAs need to be further classified for cancer. In the present study, we identified novel competing endogenous RNA (ceRNA) network for bladder cancer (BC) and explored the gene functions of the ceRNA regulatory network.MethodsDifferential gene expression analysis were performed on The Cancer Genome Atlas Urothelial Bladder Carcinoma (TCGA-BLCA) datasets to identify differentially expressed messenger RNAs (mRNAs), lncRNAs, and microRNAs (miRNAs). Based on the competing endogenous RNA (ceRNA) hypothesis, a lncRNA-miRNA-mRNA network was constructed using the StarBase database and visualization by Cytoscape software. Functional enrichment analyses of Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were performed via R package ClusterProfiler. The protein-protein interaction network was constructed by STRING database and visualization by Cytoscape. Finally, we used CIBERSORT and the TIMER database to analyze the immune infiltrations for BC.ResultsThe regulatory network was constructed via TCGA BLCA cohort. The differential expressions of lncRNA, miRNA, and mRNA were 186, 200, and 2,661, respectively. There were 106 lncRNA, miRNA, and mRNA included in the ceRNA network. In this network, Calcium Voltage-gated Channel Auxiliary Subunit Alpha2delta1 (CACNA2D1, P<0.001), domain containing engulfment adaptor1 (GULP1, P=0.001), latent transforming growth factor beta binding protein 1 (LTBP1, P=0.006), myosin light chain kinase (MYLK, P=0.001), serpin family E member 2 (SERPINE2, P=0.002), spectrin beta non-erythrocytic 2 (SPTBN2, P=0.047), and hsa-miR-590-3p (P<0.001) significantly affected the prognosis of BC patients. Functional enrichment analyses showed that the biological functions included negative regulation of protein phosphorylation, cell morphogenesis, and sensory organ morphogenesis. Important cancer pathways of KEGG included parathyroid hormone synthesis secretion action, the notch signaling pathway, MAPK signaling pathway, the Rap1 signaling pathway, signaling pathways regulating the pluripotency of stem cells, and the transforming growth factor-β signaling pathway. Our findings demonstrated that the ceRNA network has important biological functions and a significant influence on the prognosis of BC.ConclusionsThe lncRNA-miRNA-mRNA network constructed in the present study could provide useful insight into the underlying tumorigenesis of BC, and can determine new molecular biomarkers for the diagnosis and therapeutical treatment of BC.

Triple-marker immunohistochemical assessment of muscle-invasive bladder cancer: Is there prognostic significance?

BackgroundBladder cancer is the ninth most common cancer worldwide, and the third most common cancer in Lebanon. Immunohistochemistry (IHC) has been used to stratify muscle‐invasive bladder cancer (MIBC) into different subtypes. However, to our knowledge, there exists no study that investigates the use of this low‐cost technique to predict prognosis in bladder cancer patients in our region.AimTo examine the feasibility of low‐cost triple‐marker IHC assessment for MIBC subtyping in order to predict patients' survival and cisplatin sensitivity.Methods and resultsWe collected the specimens of deceased patients diagnosed with MIBC on pathology at our institution. For each case, tumor tissue blocks were retrieved and stained for hematoxylin and eosin in addition to three molecular markers by IHC: cytokeratin 5/6, cytokeratin 14 staining basal BC, and GATA3 staining luminal BC. A cut‐off of ≥20% was set as positive. Kaplan‐Meier curves were built, factored by BC subtype, to predict overall survival (OS), disease‐specific survival (DSS), and progression‐free survival (PFS). Hazard ratios in Cox regression were also created accounting for oncological factors and BC subtype.We categorized specimens as either luminal (GATA3 positive only) (n = 21; 56.7%) or as double‐positive (GATA3 and basal cytokeratin 5/6 or cytokeratin 14 positive) (n = 16; 43.3%). The overall median survival was similar between the two categories (27.0 ± 4.82 months). Numbers favored luminal disease for PFS (Breslow P = .032). After adjusting for covariates, luminal molecular expression predicted PFS (0.28; [0.09‐0.94]). Yet, the Cox model was not able to identify any predictors of OS or DSS.ConclusionSpecimens enriched with only a luminal molecular profile were more likely to exhibit cisplatin sensitivity. Despite the absence of guidelines recommending the utilization of molecular profiling in clinic practice, triple‐marker IHC could serve as a potential low‐cost prognostic indicator to identify patients at high risk of progression.

Enhanced Expression of CNTD2/CCNP Predicts Poor Prognosis in Bladder Cancer Based on the GSE13507.

Bladder cancer is one of the most common urogenital malignancies in the world, and there are no adequate prognostic indicators. CNTD2 is one of the atypical cyclins, which may be related to the cell cycle and even the development of cancers. Early studies have shown that CNTD2 is closely related to the occurrence and development of many malignant tumors. However, the mechanism of CNTD2 in bladder cancer has not been reported. In our research, we explored the different expressions of CNTD2 between 411 bladder cancers and 19 normal bladder tissues based on the TCGA dataset. CNTD2-related signaling pathways were identified through the GSEA. We analyzed the associations of CNTD2 expression and bladder cancer progression and survival using GSE13507. Compared with 19 cases of normal bladder tissue, CNTD2 gene expression was increased in 411 cases of bladder cancer. The high expression of CNTD2 strongly correlated with grade (P < 0.0001), T classification (P = 0.0001), N classification (P = 0.00011), M classification (P = 0.044), age (P = 0.027), and gender (P = 0.0012). Bladder cancer patients with high CNTD2 expression had shorter overall survival (P < 0.001). In the meantime, univariate and multivariate analyses showed that the increased expression of CNTD2 was an independent factor for poor prognosis in bladder cancer patients (P < 0.001 and P < 0.001, respectively). CNTD2 expression is closely related to bladder cancer progression, and the high expression of CNTD2 may be an adverse biomarker in bladder cancer patients.

Identification and prognostic value of a glycolysis-related gene signature in patients with bladder cancer.

Bladder cancer (BC) is one of the most common malignancies worldwide. Several biomarkers related to the prognosis of patients with BC have previously been identified. However, these prognostic models use only one gene and are thus not reliable or accurate enough. The purpose of our study was to develop an innovative gene signature that has greater prognostic value in BC. So, in this study, we performed mRNA expression profiling of glycolysis-related genes in BC (n = 407) cohorts by mining data from The Cancer Genome Atlas (TCGA) database. The glycolysis-related gene sets were confirmed using the Gene Set Enrichment Analysis (GSEA). Using Cox regression analysis, a risk score staging model was built based on the genes that were determined to be significantly associated with BC outcome. Eventually, the system of risk score was structured to predict a patient's survival, and we identified four genes (CHPF, AK3, GALK1, and NUP188) that were associated with the outcomes of BC patients. According to the above-mentioned gene signature, patients were divided into two risk subgroups. The analysis showed that our constructed risk model was independent of clinical features and that the risk score was a highly powerful tool for predicting the overall survival (OS) of BC patients. Taking together, we identified a gene signature associated with glycolysis that could effectively predict the prognosis of BC patients. Our findings offer a new perspective for the clinical research and treatment of BC.

LncRNA LINC00355 promotes EMT and metastasis of bladder cancer cells through the miR-424-5p/HMGA2 axis.

Bladder cancer is a common malignant tumor with a high recurrence rate and mortality, while the detailed mechanisms for bladder cancer progression and metastasis are unknown. Recently, long non-coding RNAs (lncRNAs) have been reported to be involved in the development of cancers. In this study, we aim to investigate the role of lncRNA LINC00355 in bladder cancer progression and metastasis. The association between LINC00355 and the prognosis of bladder cancer patients was determined by Kaplan-Meier survival analysis. Cell migration and invasion ability were detected using the Transwell migration and invasion assay. The relationships of LINC00355, miR-424-5p, and High Mobility Group AT-Hook 2 (HMGA2) were verified through the luciferase assay and RNA pull-down assay. Xenograft tumor was established to evaluate tumor lung metastasis in vivo. qRT-PCR and western blot were used to detect gene expression. LINC00355 was upregulated in bladder cancer patients, especially in patients with higher TNM stage. Elevated LINC00355 was correlated with the poor prognosis of bladder cancer patients. Besides, overexpressed LINC00355 promoted migration, invasion, and epithelial-mesenchymal transition (EMT) ability of bladder cancer cells. Contrarily, decreased LINC00355 suppressed migration, invasion, and EMT ability of bladder cancer cells, and lung metastasis of xenograft tumors. Furthermore, LINC00355 could regulate HMGA2 expression by acting as a sponge for miR-424-5p. Overexpression of HMGA2 induced EMT of bladder cancer cells. Additionally, LINC00355 regulated the migration, invasion, and EMT ability of bladder cancer cells through modulating HMGA2 expression via sponging miR-424-5p. LINC00355 promoted migration, invasion, and EMT ability of bladder cancer through elevating HMGA2 expression via acting as a sponge for miR-424-5p.

Signatures and Prognostic Values of N6-methyladenosine (m6A) - related Immune Genes in Bladder Cancer

ABSTRACT In recent years, genes associated with N6-methyladenosine (m6A) modification were found to participate in modulation of multiple tumor biological processes. Concomitantly, the significantly complicated dual effects of tumor microenvironment have been observed on cancer progression. The present study aims to investigate m6A-related immune genes (m6AIGs) for their signatures and prognostic values in bladder cancer (BC). Out of 2856 differentially expressed genes (DEGs) of BC, a total of 85 genes were obtained following intersection of DEGs, immune genes and m6A-related genes. The results of multivariate Cox regression analysis illustrated four genes (BGN, GRK5, IL32, and SREBF1) were significantly associated with the prognosis of BC patients. The BC samples were divided into two types based on the consensus clustering, and the principal component analysis demonstrated a separation between them. It was found that high expression of BGN and GRK5 were linked with advanced T and N stage, and the expression of SREBF1 in early T stage was higher than that in advanced T stage. Subsequently, the nomogram to predict 3- and 5-year survival probability of BC patients was developed and calibrated. GSEA analysis for risk subgroups showed WNT and TGF-beta signaling pathways were involved in regulation of BC progression in high risk level group. In the low risk level group, cytosolic DNA-Sensing cGAS-STING and RIG-I-like receptors signaling pathways were found to be correlated with BC development. These findings provide a novel insight on studies for BC progression.

CircRNA hsa_circ_0014130 Function as a miR-132-3p Sponge to Play an Oncogenic Role in Bladder Cancer Cells by Upregulating KCNJ12 Expression

Background: To detect the expression level of hsa_circ_0014130, and explore its biological functions and potential regulatory network in bladder cancer (BCa). Methods: The expression level of hsa_circ_0014130 was detected by qRT-PCR and its relationships to clinicopathological characteristics and prognosis of BCa patients were analyzed. The interactions between hsa_circ_0014130 and microRNA (miRNA) sponge, miRNA and its direct targets, were determined by luciferase reporter gene assay and RNA pull-down assay, and the correlations of their expression were determined by Pearson’s correlation analysis. Findings: hsa_circ_0014130 was markedly overexpressed in BCa samples and related to aggressive characteristics and poor survival. Ectopic expression of hsa_circ_0014130 markedly promoted the cell proliferation, migration, invasion and differentiation of BCa in vitro and tumor xenograft growth in vivo, while malignant biological behaviors were inhibited by hsa_circ_0014130 knockdown. There was an inverse relationship between hsa_circ_0014130 and miR-132-3p expression in BCa tissues and cells. hsa_circ_0014130 function as a competitive endogenous RNA for miR-132-3p to play oncogenic roles in BCa cells. On the other hand, KCNJ12 was a direct target of miR-132-3p at the downstream, and the expression of KCNJ12 was inversely correlated to that of miR-132-3p. Furthermore, a significantly positive correlation between hsa_circ_0014130 and KCNJ12 mRNA expression was found. More importantly, the oncogenic roles of hsa_circ_0014130 overexpression on BCa cells in vitro and in vivo were partially suppressed by ectopic expression of miR-132-3p or KCNJ12 knockdown. These findings suggested that hsa_circ_0014130 exerted its biological roles by regulating miR-132-3p/KCNJ12 expression. Further research revealed hsa_circ_0014130/miR-132-3p/KCNJ12 axis was involved in Epithelial-mesenchymal transition (EMT) process and GSK3β/AKT signaling pathway. Interpretation: hsa_circ_0014130 function as a miR-132-3p sponge to promote the oncogenesis and progression of bladder cancer by regulating KCNJ12 expression. These findings might improve the understanding of tumor pathogenesis and provide novel therapeutic targets for bladder cancer. Funding Information: None. Declaration of Interests: None. Ethics Approval Statement: The written informed consent was signed by each patient in order to notify the applying purpose of her/his tissue sample. All protocols were approved by the Ethics Committee of The Second Hospital of Tianjin Medical University.

Prediction of bladder cancer outcome by identifying and validating a mutation-derived genomic instability-associated long noncoding RNA (lncRNA) signature

ABSTRACT Bladder cancer is one of the most common malignant tumors worldwide. Accordingly, its incidence and mortality are high. One of the characteristics of cancer is genomic instability. New studies suggest that long non-coding RNAs (lncRNAs) play an important role in maintaining genomic instability. This study aimed to identify a genomic instability-associated lncRNA signature to predict the outcome of patients with bladder cancer. We downloaded data for bladder cancer patients from The Cancer Genome Atlas database to obtain lncRNA expression profiles as well as somatic mutation profiles. Using the lncRNA computational framework, a genomic instability-related lncRNA signature (GIlncSig) was established and the prognostic value of this signature was assessed and validated. A five-lncRNA signature based on genomic instability (CFAP58-DT, MIR100HG, LINC02446, AC078880.3, and LINC01833) was obtained from 58 differentially expressed lncRNAs. Patients were divided into high-risk and low-risk groups, with the high-risk group having a substantially worse prognosis than the low-risk group. Univariate and multivariate Cox analyses indicated that GIlncSig may be an independent prognostic factor; this finding was subsequently validated. In addition, enrichment analysis indicated that GIlncSig is associated with genomic instability in bladder cancer. GIlncSig has a predictive value for the prognosis of bladder cancer patients and provides guidance for the clinical treatment of these patients.

Construction of a immune-associated genes based prognostic signature in bladder cancer

Current studies indicated that immune-associated genes (IAGs) have important roles in the occurrence and development of bladder cancer (BC). The current work aims to identify the prognostic values of IAGs in BC and establish a prognostic signature based on IAGs. RNA sequencing data and protein expression data were used to identify differentially expressed IAGs in BC. An IAGs based signature was further constructed and the prognostic and predictive values of the signature were evaluated by survival analysis and nomogram. RNA isolation and reverse transcription-quantitative PCR (RT-qPCR) were further performed to investigate the expression levels of IAGs in BC cells and were used to explore the relationship between IAGs and M2 tumour-associated macrophages (TAMs) secreted transforming growth factor-β1 (TGF-β1) in BC cells. We selected five IAGs to develop an IAGs signature model, which were significantly related to survival outcomes of BC patients. RT-qPCR showed that five IAGs were significantly differentially expressed and three IAGs were positively correlated with M2 TAMs secreted TGF-β1 in T24 cells. We identified and validated an IAGs based signature to predict the prognosis of BC patients. Furthermore, M2 TAMs may promote the expression of IAGs in BC via the TGF-β1 signalling pathway.

WITHDRAWN: Novel diagnostic and prognostic value of circulating miR-18a in the plasma of patients with bladder cancer

MiR-18a has been reported in many cancer types, including prostate cancer, gastric cancer, nasopharyngeal carcinoma, esophageal squamous cell carcinoma and breast cancer. Nevertheless, the role of miR-18a remains unclear in bladder cancer. The expression of miR-18a in bladder cancer tissues was evaluated by qRT-PCR. The diagnostic value of plasma miR-18a was detected by receiver operating characteristic (ROC) analysis. Survival analysis was performed using Kaplan-Meier, and the prognostic significance of miR-18a was analyzed using Cox regression analysis. MiR-18a was observed to be upregulated in human bladder cancer tissues. Moreover, the expression of plasma miR-18a was found to be closely associated with tumor type, histological grade, TNM stage and tumor size. High expression of miR-18a was found to be capable of predicting unfavorable clinical prognosis in bladder cancer patients. Notably, plasma miR-18a expression was shown to exhibit fundamental diagnostic significance in discriminating bladder cancer patients from healthy individuals, and in differentiating muscle invasive bladder cancer (MIBC) from non-muscle invasive bladder cancer (NMIBC). This study demonstrated that miR-18a is a potential diagnostic biomarker associated with the prognosis of bladder cancer patients. Hence, miR-18a may be a useful biomarker for the screening of bladder cancer.

Prognostic value of the miR-200 family in bladder cancer: A systematic review and meta-analysis.

Background:We aimed to evaluate the prognostic significance of high expression of the miR-200 family of microRNAs in bladder cancer.Methods:Studies on the correlation between the miR-200 family and prognosis in patients with bladder cancer were searched in databases. Combined hazard ratios (HRs) were calculated based on HRs and 95% confidence intervals (CIs) for overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS). Cochranes Q test and the I2 statistic were utilized to assess heterogeneity across the included studies. Potential publication bias was analyzed by Begg and Egger tests. The meta-analysis was conducted using RevMan 5.3 and Stata SE12.0.Results:Data from a total of 1150 patients from 8 studies were extracted. The meta-analysis revealed that high expression of the miR-200 family was correlated with better OS (pooled hazard ratio: 0.50, 95% confidence interval: 0.40–0.62), CSS (pooled hazard ratio: 0.36, 95% confidence interval: 0.22–0.59) and RFS (pooled hazard ratio: 0.48, 95% confidence interval: 0.36–0.65). Both Begg test and Egger test verified no publication bias within the included cohorts.Conclusion:The high expression of the miR-200 family is strongly associated with better prognosis in bladder cancer patients, which will improve bladder cancer management in clinical practice.

Identification and verification of an immune-related lncRNA signature for predicting the prognosis of patients with bladder cancer

BackgroundRecent studies have revealed the significant roles of immune-related long noncoding RNAs (lncRNAs) in cancer development and progression. The identification of biomarkers that contribute to early detection and risk stratification provides significant benefits for bladder cancer (BC) patients. The current study aimed to determine an immune-related lncRNA signature for predicting the prognosis of BC patients. MethodsBased on The Cancer Genome Atlas (TCGA) database, we identified seven immune-related lncRNAs with prognostic value. The predictive value of the prognostic signature developed from immune-related lncRNAs was assessed by survival and nomogram analyses. Principal component analysis (PCA) was performed to visualize gene expression patterns in the groups defined by the risk score, and the immune composition and purity of the tumor were evaluated by the ESTIMATE algorithm. ResultsBased on the Pearson correlation analysis results, 765 immune-related lncRNAs were filtered (|R| > 0.4, P < 0.001), and seven immune-related lncRNAs (Z84484.1, AC009120.2, AL450384.2, AC024060.1, TNFRSF14-AS1, AL354919.2, OCIAD1-AS1) with prognostic value were finally identified. Patients in the low-risk group had a better prognosis than those in the high-risk group. Multivariate Cox regression analysis showed that the signature was an independent prognostic factor. A prognostic nomogram with clinical features and the signature of seven immune-related lncRNAs was also constructed. According to the PCA and ESTIMATE algorithm results, we found different immune statuses in the low-and high-risk groups. ConclusionsOur study shows that the signature of seven immune-related lncRNAs can be used as a prognostic marker for BC.

Autophagy-related long noncoding RNAs can predict prognosis in patients with bladder cancer.

We investigated whether autophagy-related long noncoding RNAs (lncRNAs) can predict prognosis in bladder cancer. We obtained bladder cancer lncRNA data from The Cancer Genome Atlas and autophagy-related genes from the Human Autophagy Database. Fifteen autophagy-related lncRNAs with prognostic significance were identified. Multivariate Cox analysis was used to construct a risk score model, which divided bladder cancer patients into high-risk and low-risk groups. We found that patients in the low-risk group had better survival than those in the high-risk group. Subgroup analysis showed that patients in the high-risk group also had worse OS than that in the low-risk group in subgroups based on age, gender, clinical stage, and TNM stage. We next established a nomogram according to the results of multivariate Cox regression, which included age, gender, clinical stage, TNM stage, and risk score. The area under the curve for 3- and 5-year overall survival predicted by the nomogram were 0.711 and 0.719, respectively. Bioinformatics analysis demonstrated that the 15 identified lncRNAs are involved in the cell cycle, DNA replication, cell adhesion, cancer pathway, WNT signaling pathway, and oxidative stress. These findings confirm that autophagy-related lncRNAs are predictive of prognosis in bladder cancer patients and may affect tumor progression.