Mitofusin-2 Down-Regulation Predicts Progression of Non-Muscle Invasive Bladder Cancer.
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ABSTRACT:
SUBMITTER: Cormio A
PROVIDER: S-EPMC8394056 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Purpose: Bladder cancer (BCa) is generally considered one of the most prevalent deadly diseases worldwide. Patients suffering from muscle-invasive bladder cancer (MIBC) possess dismal prognoses, while those with non-muscle-invasive bladder cancer (NMIBC) generally have a favorable outcome after local treatment. However, some NMIBCs relapse and progress to MIBC, with an unclarified mechanism. Hence, insight into the genetic drivers of BCa progression has tremendous potential benefits for precision therapeutics, risk stratification, and molecular diagnosis. Methods: In this study, three cohorts profile datasets (GSE13507, GSE32584, and GSE89) consisting of NMIBC and MIBC samples were integrated to address the differently expressed genes (DEGs). Subsequently, the protein-protein interaction (PPI) network and pathway enrichment analysis of DGEs were performed. Results: Six collagen members (COL1A1, COL1A2, COL5A2, COL6A1, COL6A2, and COL6A3) were up-regulated and gathered in the ECM-receptor interaction signal pathway identified by KEGG pathway analysis and GSEA. Evidence derived from the Oncomine and TCGA databases indicated that the 6 collagen genes promote the progression of BCa and are negatively associated with patient prognosis. Moreover, taking COL1A1 as a further research object, the results showed that COL1A1 was up-regulated in MIBC and its knockdown significantly inhibited the proliferation, migration, and invasion of 5637 and T24 cells by inhibiting epithelial-mesenchymal transition (EMT) process and the TGF-β signaling pathway. Conclusion: With integrated bioinformatic analysis and cell experiments, we showed that 6 collagen family members are high progression risk factors and that they can be used as independent effective diagnostic and prognostic biomarkers for BCa.
| S-EPMC6511250 | biostudies-literature
Project description:There are no reliable criteria to handle disease progression of muscle invasive bladder cancer (MIBC), which strongly influences patient survival. Therefore, an accurate predicting method to identify progressive MIBC patients is greatly needed. The aim of this study was to identify a genetic signature associated with disease progression in MIBC. To address this issue, we analyzed three independent cohorts (a training set, test set 1 and test set 2) comprising a total of 128 MIBC patients. Microarray gene expression profiling, including gene network analysis, was performed in the training set to identify a gene expression signature associated with disease progression. The prognostic value of the signature was validated in test set 1 and test set 2 by microarray and real-time reverse transcriptase polymerase chain reaction (RT-PCR), respectively. The determination of gene expression patterns by microarray data analysis identified 1,320 genes associated with disease progression. Gene network analysis of the 1,320 genes suggested that IL1B, S100A8, S100A9 and EGFR were important mediators of MIBC progression. We validated this putative four-gene signature in two independent cohorts (log-rank test, P < 0.05 each, respectively) and estimated the predictive value of the signature by multivariate Cox regression analysis (hazard ratio [HR], 6.24; 95% confidence interval [CI], 1.58-24.61; P = 0.009). Finally, signature-based stratification demonstrated that the four-gene signature was an independent predictor of MIBC progression. In conclusion, a molecular signature defined by four genes represents a promising diagnostic tool for the identification of MIBC patients at high risk of progression.
| S-EPMC3105150 | biostudies-literature
Project description:ObjectivesTo evaluate the protein expression of connexin 43 (Cx43) in primary urothelial bladder cancer and test its association with the histopathological characteristics and clinical outcome.MethodsA tissue microarray containing 348 tissue samples from 174 patients with primary urothelial carcinomas of the bladder was immunohistochemically stained for Cx43. The intensity of staining was semiquantitatively evaluated (score 0, 1+, 2+), and the association with clinicopathological features was assessed. Univariable and multivariable analyses were performed to identify predictors for progression-free survival (PFS).ResultsMembranous Cx43 immunoreactivity was detected in 118 (67.8%) of 174 analysable urothelial carcinomas, of which 31 (17.8%) showed even a strong (score 2+) and mainly homogeneous staining. Strong expression levels of Cx43 (score 2+) were associated with higher tumour grade, multiplicity and increased proliferation (all p<0.05). In the subgroup of patients with stage pTa and pT1 bladder tumours (n=158), strong Cx43 expression (p<0.001), solid growth pattern (p<0.001) and increased Ki-67 proliferation fraction (p<0.05) were significantly associated with shorter PFS in an univariable Cox regression analysis. In multivariable Cox regression models, Cx43 immunoreactivity and histological growth pattern remained highly significant and adverse risk factors for PFS.ConclusionsThe expression levels of Cx43 are frequent in non-muscle invasive bladder cancer (NMIBC), with high expression levels being associated with poor prognosis. Routine assessment of Cx43 expression may improve the identification of high-risk NMIBC.
| S-EPMC4602233 | biostudies-literature
Project description:Non-muscle-invasive bladder cancer (NMIBC) is a common disease with a high recurrence rate requiring lifetime surveillance. Although NMIBC is not life-threatening, it can progress to muscle-invasive bladder cancer (MIBC), a lethal form of the disease. The management of the two diseases differs, and patients with MIBC require aggressive treatments such as chemotherapy and radical cystectomy. NMIBC patients at a high risk of progression benefit from early immediate cystectomy. Thus, identifying concordant markers for accurate risk stratification is critical to predict the prognosis of NMIBC. Candidate genetic biomarkers associated with NMIBC prognosis were screened by RNA-sequencing of 24 tissue samples, including 16 NMIBC and eight normal controls, and by microarray analysis (GSE13507). Lastly, we selected and investigated a mitotic checkpoint serine/threonine kinase, BUB1, that regulates chromosome segregation during the cell cycle. BUB1 gene expression was tested in 86 NMIBC samples and 15 controls by real-time qPCR. The performance of BUB1 as a prognostic biomarker for NMIBC was validated in the internal Chungbuk cohort (GSE13507) and the external UROMOL cohort (E-MTAB-4321). BUB1 expression was higher in NMIBC patients than in normal controls (p < 0.05), and the overexpression of BUB1 was correlated with NMIBC progression (log-rank test, p = 0.007). In in vitro analyses, BUB1 promoted the proliferation of bladder cancer cells by accelerating the G2/M transition of the cell cycle. Conclusively, BUB1 modulates the G2/M transition to promote the proliferation of bladder cancer cells, suggesting that it could serve as a prognostic marker in NMIBC.
| S-EPMC8657483 | biostudies-literature
Project description:BackgroundNon-muscle invasive bladder neoplasms with invasion of the lamina propria (stage T1) or high grade of dysplasia are at "high risk" of progression to life-threatening cancer. However, the individual course is difficult to predict. Chromosomal instability (CI) is associated with high tumor stage and grade, and possibly with the risk of progression.MethodsTo investigate the relationship between CI and subsequent disease progression, we performed a case-control-study of 125 patients with "high-risk" non-muscle invasive bladder neoplasms, 67 with later disease progression, and 58 with no progression. Selection criteria were conservative (non-radical) resections and full prospective clinical follow-up (> 5 years). We investigated primary lesions in 59, and recurrent lesions in 66 cases.We used Affymetrix GeneChip Mapping 10 K and 50 K SNP microarrays to evaluate genome wide chromosomal imbalance (loss-of-heterozygosity and DNA copy number changes) in 48 representative tumors. DNA copy number changes of 15 key instability regions were further investigated using QPCR in 101 tumors (including 25 tumors also analysed on 50 K SNP microarrays).ResultsChromosomal instability did not predict any higher risk of subsequent progression. Stage T1 and high-grade tumors had generally more unstable genomes than tumors of lower stage and grade (mostly non-primary tumors following a "high-risk" tumor). However, about 25% of the "high-risk" tumors had very few alterations. This was independent of subsequent progression. Recurrent lesions represent underlying field disease. A separate analysis of these lesions did neither reflect any difference in the risk of progression. Of specific chromosomal alterations, a possible association between loss of chromosome 8p11 and the risk of progression was found. However, the predictive value was limited by the heterogeneity of the changes.ConclusionChromosomal instability (CI) was associated with "high risk" tumors (stage T1 or high-grade), but did not predict subsequent progression. Recurrences after "high-risk" tumors had fewer chromosomal alterations, but there was no association with the risk of progression in this group either. Thus, the prediction of progression of "high risk" non-muscle invasive bladder tumors using chromosomal changes is difficult. Loss of chromosome 8p11 may play a role in the progression process. About 25% of the "high risk" tumors were chromosomal stable.
| S-EPMC2696467 | biostudies-literature
Project description:PurposeNon-muscle invasive bladder cancers (NMIBC) are generally curable, while ~15% progresses into muscle-invasive cancer with poor prognosis. While efforts have been made to identify genetic alternations associated with progression, the extracellular matrix (ECM) microenvironment remains largely unexplored. Type I collagen is a major component of the bladder ECM, and can be altered during cancer progression. We set out to explore the association of type I collagen with NMIBC progression.Experimental designThe associations of COL1A1 and COL1A2 mRNA levels with progression were evaluated in a multi-center cohort of 189 patients with NMIBCs. Type I collagen protein expression and structure were evaluated in an independent single-center cohort of 80 patients with NMIBCs. Immunohistochemical analysis was performed and state-of-the-art multi-photon microscopy was used to evaluate collagen structure via second harmonic generation imaging. Progression to muscle invasion was the primary outcome. Kaplan-Meier method, Cox regression, and Wilcoxon rank-sum were used for statistical analysis.ResultsThere is a significant association of high COL1A1 and COL1A2 mRNA expression in patients with poor progression-free survival (P=0.0037 and P=0.011, respectively) and overall survival (P=0.024 and P=0.012, respectively). Additionally, immunohistochemistry analysis of type I collagen protein deposition revealed a significant association with progression (P=0.0145); Second-harmonic generation imaging revealed a significant lower collagen fiber curvature ratio in patients with invasive progression (P = 0.0018).ConclusionsAlterations in the ECM microenvironment, particularly type I collagen, likely contributes to bladder cancer progression. These findings will open avenues to future functional studies to investigate ECM-tumor interaction as a potential therapeutic intervention to treat NMIBCs.
| S-EPMC5347718 | biostudies-literature
Project description:BACKGROUND: While several molecular markers of bladder cancer prognosis have been identified, the limited value of current prognostic markers has created the need for new molecular indicators of bladder cancer outcomes. The aim of this study was to identify genetic signatures associated with disease prognosis in bladder cancer. RESULTS: We used 272 primary bladder cancer specimens for microarray analysis and real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis. Microarray gene expression analysis of randomly selected 165 primary bladder cancer specimens as an original cohort was carried out. Risk scores were applied to stratify prognosis-related gene classifiers. Prognosis-related gene classifiers were individually analyzed with tumor invasiveness (non-muscle invasive bladder cancer [NMIBC] and muscle invasive bladder cancer [MIBC]) and prognosis. We validated selected gene classifiers using RT-PCR in the original (165) and independent (107) cohorts. Ninety-seven genes related to disease progression among NMIBC patients were identified by microarray data analysis. Eight genes, a progression-related gene classifier in NMIBC, were selected for RT-PCR. The progression-related gene classifier in patients with NMIBC was closely correlated with progression in both original and independent cohorts. Furthermore, no patient with NMIBC in the good-prognosis signature group experienced cancer progression. CONCLUSIONS: We identified progression-related gene classifier that has strong predictive value for determining disease outcome in NMIBC. This gene classifier could assist in selecting NMIBC patients who might benefit from more aggressive therapeutic intervention or surveillance.
| S-EPMC2821358 | biostudies-literature
Project description:Although non muscle-invasive bladder cancer can be treated successfully by surgical resection, there is a high rate of recurrence, which frequently develops into an invasive form of cancer. Due to the lack of marker molecules to predict recurrence, it is currently recommended that after resection each patient is screened via cystoscopy at least twice a year. This results in a psychic burden to the patient and substantial economic costs to the health care system. Using antibody microarrays targeting 724 different cancer-related proteins, we studied protein profiles of patients with and without recurrence. The analysis revealed 255 proteins of differential abundance. Most are involved in the regulation and execution of apoptosis and cell proliferation. For prognosis, a signature of 20 proteins was determined that predicts bladder cancer recurrence with 100% sensitivity and 80% specificity. As a measure of overall accuracy, the area under the curve (AUC) value was found to be 90%. This is well within a clinically relevant window of quality and should support decision making about the stringency of surveillance or even different treatment options.
2014-04-07 | E-MEXP-3625 | biostudies-arrayexpress
Project description:The prediction of the response to Bacillus Calmette-Guerin (BCG) can help identify non-muscle-invasive bladder cancer (NMIBC) patients that may be better served with alternative therapy. Several cytokine profiles present promising results, but they are difficult to use in clinical practice. In this prospective, longitudinal study, we tried to identify reliable serum cytokines/chemokines to predict the response to BCG using samples collected before and during BCG induction therapy. We used the Bio-plex multiplex assays to identify potential BCG failure-related serum cytokines/chemokines in the discovery set (n = 13). After screening, we identified CCL27 as the top candidate biomarker for predicting the response to BCG (P = .003). In the validation set, we found that the AUC of the baseline CCL27 was 0.730 (95% CI 0.515-0.945, P = .040) along with 67% sensitivity, 78% specificity. The changes from baseline to last timepoint can also distinguish BCG responders from non-responders (AUC: 0.726, 95% CI 0.474-0.979, P = .044). Moreover, the combination score of serum CCL27 (CSCCL27), based on the baseline and changes of CCL27, could further improve the predictive accuracy with an AUC of 0.897 (95% CI 0.790-1.000, P < .001). The correlations between CCL27 and local/systemic immunologic parameters were further analyzed. The level of serum CCL27 was strongly correlated with regulatory T cells (Tregs) in the tumor microenvironment (P = .002), indicating that CCL27 may promote the recruitment of Tregs into the tumor microenvironment. Our results show that serum CCL27 may represent a practical and reliable marker for the prediction of the response to BCG in NMIBC.
| S-EPMC7458591 | biostudies-literature
Project description:BACKGROUND:The high rate of non-muscle-invasive bladder cancer recurrence is a major challenge in patient management. miRNAs functionally regulate tumor cell proliferation and invasion, and have strong potential as biomarkers because they are robust to degradation. The objective of this project was to identify reproducible prognostic miRNAs in resected non-muscle-invasive bladder tumor tissue that are predictive of the recurrent tumor phenotype. METHODS:We utilized patients diagnosed with primary non-muscle-invasive bladder cancer in three independent cohorts for a biomarker discovery/validation approach. Baseline tumor tissue from patients with the clinically challenging, non-muscle-invasive primary low stage (Ta), high grade, and T1 tumors (tumors extending into the lamina propria) comprised the discovery cohort (n = 38). We isolated the tumor tissue RNA and assessed a panel of approximately 800 miRNAs. RESULTS:miR-26b-5p was the top-ranking prognostic tumor tissue miRNA, with a time-to-recurrence HR 0.043 for levels above versus below median, (P adj = 0.0003). miR-26b-5p was related to a dose-response reduction in tumor recurrence, and levels above the median were also associated with reduced time-to-progression (P adj = 0.02). We used two independent longitudinal cohorts that included both low-grade and high-grade Ta and T1 tumors for validation and found a consistent relationship between miR-26b-5p and recurrence and progression. CONCLUSIONS:Our results suggest that miR-26b-5p levels may be prognostic for non-muscle-invasive bladder cancer recurrence, and can feasibly be assessed in baseline tumor tissue from a wide variety of clinical settings. IMPACT:Early identification of those non-muscle-invasive bladder tumor patients with refractory phenotypes would enable individualized treatment and surveillance.
| S-EPMC6473178 | biostudies-literature