Transcriptomic Analysis Identified ARHGAP Family as a Novel Biomarker Associated With Tumor-Promoting Immune Infiltration and Nanomechanical Characteristics in Bladder Cancer.
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SUBMITTER: Yang C
PROVIDER: S-EPMC8294098 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Bladder cancer is a very common malignancy. Although new treatment strategies have been developed, the identification of new therapeutic targets and reliable diagnostic/prognostic biomarkers for bladder cancer remains a priority. Generally, they are found among differentially expressed genes between patients and healthy subjects or among patients with different tumor stages. However, the classical approach includes processing these data taking into consideration only the expression of each single gene regardless of the expression of other genes. These complex gene interaction networks can be revealed by a recently developed systems biology approach called Weighted Gene Co-expression Network Analysis (WGCNA). It takes into account the expression of all genes assessed in an experiment in order to reveal the clusters of co-expressed genes (modules) that, very probably, are also co-regulated. If some genes are co-expressed in controls but not in pathological samples, it can be hypothesized that a regulatory mechanism was altered and that it could be the cause or the effect of the disease. Therefore, genes within these modules could play a role in cancer and thus be considered as potential therapeutic targets or diagnostic/prognostic biomarkers. Here, we have reviewed all the studies where WGCNA has been applied to gene expression data from bladder cancer patients. We have shown the importance of this new approach in identifying candidate biomarkers and therapeutic targets. They include both genes and miRNAs and some of them have already been identified in the literature to have a role in bladder cancer initiation, progression, metastasis, and patient survival.
| S-EPMC6194189 | biostudies-literature
Project description:BackgroundThe tumor microenvironment (TME) plays a crucial role in the initiation and progression of cancer. Bladder cancer (BLCA) is a malignant tumor of the genitourinary system. Its heterogeneity results in significant differences in the prognosis of patients. To date, this is still a huge challenge for clinical treatment. In recent years, more and more evidence showed that dysregulation of transcription factors (TFs) plays an important role in tumor progression, invasion, and metastasis. Unfortunately, the role of TFs on the tumor microenvironment in bladder cancer is unclear.MethodsThe original data of BLCA and corresponding adjacent tissues were obtained from The Cancer Genome Atlas (TCGA) database. TFs were downloaded from the Animal Transcription Factor DataBase (Animal TFDB). Intersection analysis was used to obtain TFs that were differentially expressed between tumor and adjacent tissues. Gene Set Cancer Analysis (GSCALite) and CIBERSORT software were used to reveal the key differentially expressed TFs (DE-TFs). Subsequently, UALCAN and Human Protein Atlas (HPA) databases were used to disclose the expression of key DE-TFs in BLCA. The K-M curve divulged the relationship between the key DE-TFs and the patient's overall survival (OS), and the univariate and multivariate Cox regression analyses were conducted to explore independent prognostic factors. The cluster profiler package and Gene Set Enrichment Analysis (GSEA) were used for functional enrichment of genes related to the key DE-TFs. Finally, CIBERSORT software analyzed the immune landscape of BLCA.ResultsWe obtained a total of 117 BLCA-related DE-TFs. Among them, ETV7 was identified as the key DE-TFs due to its association with the autophagy activation pathway and various immune cells in cancer. Online databases of UALCAN and HPA indicated that ETV7 was overexpressed in tumors and negatively correlated with tumor severity. The K-M curve showed that the OS of patients with high expression of ETV7 was poor, which indicated that it was an independent prognostic factor. Functional enrichment of 87 DEGs between ETV7-high and -low expression groups indicated that it was closely related to the immune response and the functions of a variety of immune cells. Finally, CIBERSORT results proved that the high and low expression of ETV7 also caused significant differences in the tumor immune microenvironment of patients.ConclusionOverall, we proved that the transcription factor ETV7 was a novel prognostic factor, which may improve the individualized outcome prediction in BLCA by regulating the tumor immune microenvironment.
| S-EPMC8678556 | biostudies-literature
Project description:Background: Transcriptional factors (TFs) are responsible for regulating the transcription of pro-oncogenes and tumor suppressor genes in the process of tumor development. However, the role of these transcription factors in Bladder cancer (BCa) remains unclear. And the main purpose of this research is to explore the possibility of these TFs serving as biomarkers for BCa. Methods: We analyzed the differential expression of TFs in BCa from The Cancer Genome Atlas (TCGA) online database, identified 408 up-regulated TFs and 751down-regulated TFs. We obtained some hub genes via WGCNA model and detected the RNAs level in BCa cells and tissues. Then, the relationship between the expression and clinicopathological parameters was further investigated. Kaplan-Meier curves and the log-rank test were carried out to analyze the relationship between NFATC1, AKNA and five-TFs combination and overall survival (OS). And RT-PCR assay was conducted to further consolidate and verify these results. Results: There were significant differences in the expression of five TFs (CBX7, AKNA, HDAC4, EBF2 and NFATC1) between bladder cancer and normal bladder tissue. In BCa tissue and cell lines, the five TFs were frequently down-regulated, and closely related to poor prognosis. Moreover, the RT-PCR results of five TFs in bladder cancer and normal bladder tissue were consistent with the database results, and reduced TFs could significantly induce or restrain the transcription of many critical factors. The expression level of AKNA and NFATC1 could serve as independent biomarker to predict the overall survival (P<0.05). And the above five TFs combined detection of bladder cancer has higher sensitivity and specificity. Furthermore, differential neutrophils expression between high-risk and low-risk were found, which consolidated the role and function of the five TFs combination model in the progression of BCa. Conclusions: Our analysis effectively provides a newly TFs-associated prognostic model for bladder cancer. The combination of five identified-TFs is an independent prognostic biomarker, which could serve as a more effective therapeutic target for BCa patients.
| S-EPMC8364643 | biostudies-literature
Project description:BackgroundBrain tumor ranks as the most devastating cancer type. The complex tumor immune microenvironment prevents brain tumor from receiving therapeutic benefits. The purpose of this study was to stratify brain tumors based on their distinct immune infiltration signatures to facilitate better clinical decision making and prognosis prediction.MethodsWe developed a deep learning model to characterize immune infiltration from transcriptome. The developed model was applied to distill expression signatures of transcriptome of brain tumor samples. We performed molecular subtyping with the extracted expression signatures to unveil brain tumor subtypes. Computational methods, including gene set enrichment analysis, Kaplan-Meier survival and multivariate Cox regression analyses, were employed.ResultsWe identified two distinctive subtypes (i.e. C1/2) of brain tumor featured by distinct immune infiltration signatures. The C1 subtype is characterized by protective immune infiltration signatures, including high infiltration of CD8+ T cells and activation of CX3CL1. The C2 subtype has an extensive infiltration of tumor-associated macrophages and microglia, and was enriched with immune suppressive, wound-healing, and angiogenic signatures. The C1 subtype had significantly better prognosis as compared with C2 (Log-rank test, HR: 2.5, 95% CI: 2.2 - 2.7; P = 8.2e-78). This difference remained statistically significant (multivariate Cox model, HR: 2.2, 95% CI: 1.7 - 2.9; P = 3.7e-10) by taking into account age, gender, recurrent/secondary status at sampling time, tumor grade, histology, radio-chemotherapy, IDH mutation, MGMT methylation, and co-deletion of 1p and 19q. This finding was validated in six datasets. The C2 subtype of glioblastoma patients with IDH mutation has poor survival analogous to those without IDH mutation (Log-rank test, adjusted P = 0.8), while C1 has favorable prognosis as compared with glioblastoma of C2 subtype with IDH mutation (Log-rank test, adjusted P = 1.2e-3) or without IDH mutation (Log-rank test, adjusted P = 1.3e-6).ConclusionsWe identified two distinctive subtypes of brain tumor with different immune infiltration signatures, which might be helpful as an independent prognosticator for brain tumor.
| S-EPMC8554158 | biostudies-literature
Project description:The Schlafen (SLFN) gene family plays an important role in immune cell differentiation and immune regulation. Previous studies have found that the increased SLFN5 expression in patients with intestinal metaplasia correlates with gastric cancer (GC) progression. However, no investigation has been conducted on the SLFN family in GC. Therefore, we systematically explore the expression and prognostic value of SLFN family members in patients with GC, elucidating their possible biological function and its correlation with tumor immune cells infiltration. TCGA database results indicated that the SLFN5, SLFN11, SLFN12, SLFN12L, and SLFN13 expression was significantly higher in GC. The UALCAN and KM plotter databases indicated that enhanced the SLFN family expression was associated with lymph node metastasis, tumor stage, and tumor grade and predicted an adverse prognosis. cBioportal database revealed that the SLFN family had a high frequency of genetic alterations in GC (about 12%), including mutations and amplification. The GeneMANIA and STRING databases identified 20 interacting genes and 16 interacting proteins that act as potential targets of the SLFN family. SLFN5, SLFN11, SLFN12, SLFN12L, and SLFN14 may be implicated in the immunological response, according to Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Additionally, Timer and TISIDB databases indicate that SLFN5, SLFN11, SLFN12, SLFN12L, and SLFN14 are involved in the immune response. Furthermore, Timer, TCGA, and TISIDB databases suggested that the SLFN5, SLFN11, SLFN12, SLFN12L, and SLFN14 expression in GC is highly linked with immune cell infiltration levels, immune checkpoint, and the many immune cell marker sets expression. We isolated three samples of peripheral blood mononuclear cell (PBMC) and activated T cells; the results showed the expression of SLFN family members decreased significantly when T cell active. In conclusion, the SLFN family of proteins may act as a prognostic indicator of GC and is associated with immune cell infiltration and immune checkpoint expression in GC. Additionally, it may be involved in tumor immune evasion by regulating T cell activation.
| S-EPMC9452737 | biostudies-literature
Project description:KDELR2 has been reported as a promotive factor for the genesis and progression of several malignancies. However, it is uncertain how it affects bladder urothelial carcinoma (BLCA). Using data extracted from online databases, an enhanced expression of KDELR2 in BLCA tissues was verified. Overexpression of KDELR2 was correlated with advanced clinicopathologic characteristics and unfavourable prognosis of BLCA. Receiver operating characteristic analysis highlighted the potential diagnostic value of KDELR2. Univariate and multivariate logistic regression analyses further revealed the predictive effect of KDELR2 for the prognosis of BLCA. KDELR2 was primarily enriched in biological functions related to organization of the extracellular matrix. TIMER, ssGSEA and GEPIA analyses suggested that KDELR2 expression is positively related to the infiltration of macrophages, Th2 cells and neutrophils. Finally, knocking-down of KDELR2 in T24 cells resulted in reduced proliferation, migration and macrophages recruitment. These results suggest that KDELR2 overexpression is an indicator for poor prognosis of BLCA and it has the potential to be employed as an immunotherapy target for BLCA.
| S-EPMC10548500 | biostudies-literature
Project description:BackgroundCLDN5 protein is essential for the formation of tight junctions in epithelial cells, and has been associated with epithelial-mesenchymal transition. Research has indicated that CLDN5 is associated with tumor metastasis, the tumor microenvironment, and immunotherapy in multiple types of cancer. Also, no comprehensive evaluation of the expression of CLDN5 and immunotherapy signatures through a pan-cancer analysis or immunoassay has been performed.MethodsWe explored CLDN5's differential expression, survival analysis and clinicopathological staging through the TCGA database, and then corroborated the expression of CLDN5 by utilizing the GEO (Gene expression omnibus) database. To analyze CLDN5 KEGG, GO, and Hallmark mutations, as well as TIMER for immune infiltration, GSEA was utilized with ROC curve, mutation, and other factors such as survival, pathological stage, TME, MSI, TMB, immune cell infiltration, and DNA methylation. Immunohistochemistry was used to assess CLDN5 staining in gastric cancer tissues and paracancerous tissues. Visualization was done with R version 4.2.0 (http://www.rproject.org/).ResultsAccording to TCGA database, CLDN5 expression levels differed significantly between cancer and normal tissues, and the GEO database (GSE49051 and GSE 64951) and tissue microarrays confirmed this result. Infiltrating cluster of differentiation 8+ (CD8+) T cells, CD4+ cells, neutrophils, dendritic cells, and macrophages revealed a correlation with CLDN5 expression. DNA methylation, TMB, and MSI are related to CLDN5 expression. Based on the ROC curve analysis, CLDN5 demonstrates outstanding diagnostic effectiveness for gastric cancer and is comparable to CA-199.ConclusionsThe findings suggest that CLDN5 is implicated in the oncogenesis of diverse cancer types, underscoring its potential significance in cancer biology. Notably, CLDN5 could have implications in immune filtration and immune checkpoint inhibitor therapies, however, further research is needed to confirm this.
| S-EPMC10292893 | biostudies-literature
Project description:BackgroundStanniocalcin-1 (STC1) is a well-studied oncogene that promotes different types of cancer progression. However, the expression status of STC1, the values of STC1 on prognosis, and its immune characteristic in bladder cancer (BLCA) have not been well examined.MethodsThe expression of STC1 and its clinicopathological as well as immune characteristics in BLCA samples were firstly identified in The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Immunohistochemistry (IHC) performed on the tissue microarray (TMA) slide was further used to validate the expression of STC1 and its relationship with immune features in 16 non-muscle invasive bladder cancer (NMIBC) samples and 42 muscle invasive bladder cancer (MIBC) samples.ResultsThe expression of STC1 was upregulated in higher stage BLCA. High STC1 expression also predicted poor prognosis in BLCA. Subsequently, the TMA validated the expression and prognostic value of STC1 in BLCA. Bioinformatics analysis demonstrated that STC1 and common immune checkpoints as well as immune markers of various immune cells were positively correlated in TCGA. In addition, IHC data from the TMA further validated that tumor cells with higher STC1 level tended to express higher PDL1 as well as increased infiltration of CD3+ T cells.ConclusionTo our knowledge, this is the first comprehensive study that investigates the clinical and immune characteristics of STC1 in BLCA. It may provide new insight into the function of STC1 in regulating tumor immune microenvironment. Further studies are warranted to uncover the potential mechanisms that mediate STC1 expression and tumor immunity in BLCA.
| S-EPMC8445105 | biostudies-literature
Project description:As one of the common malignancies that threaten human life, bladder cancer occurs frequently with a high mortality rate in the world, due to its invasion, recurrence and drug resistance. Natural products from marine microorganisms are becoming the hotspots in discovery of new candidate drug entities, especially in the area of cancer. Brefeldin A (BFA) is a natural Arf-GEFs inhibitor, but due to the low aqueous solubility, strong toxicity, and poor bioavailability, it is urgent to conduct structural optimization research. Herein, a new BFA pyridine acrylate derivative CHNQD-01281 with improved solubility was prepared and found to exert moderate to strong antiproliferative activity on a variety of human cancer cell lines. It was noteworthy that CHNQD-01281 was most sensitive to two bladder cancer cell lines T24 and J82 (IC50 = 0.079 and 0.081 μmol/L) with high selectivity index (SI = 14.68 and 14.32), suggesting a superior safety to BFA. In vivo studies revealed that CHNQD-01281 remarkably suppressed tumor growth in a T24 nude mice xenograft model (TGI = 52.63%) and prolonged the survival time (ILS = 68.16%) in an MB49 allogeneic mouse model via inducing infiltration of cytotoxic T cells. Further mechanism exploration indicated that CHNQD-01281 regulated both EGFR/PI3K/AKT and EGFR/ERK pathways and mediated the chemotactic effect of chemokines on immune effector cells. Overall, CHNQD-01281 may serve as a potential therapeutic agent for bladder cancer through multiple mechanisms.Supplementary informationThe online version contains supplementary material available at 10.1007/s42995-024-00246-w.
| S-EPMC11358582 | biostudies-literature
Project description:BackgroundGestational diabetes mellitus (GDM) is a type of glucose intolerance disorder that first occurs during women's pregnancy. The main diagnostic method for GDM is based on the midpregnancy oral glucose tolerance test. The rise of metabolomics has expanded the opportunity to better identify early diagnostic biomarkers and explore possible pathogenesis.MethodsWe collected blood serum from 34 GDM patients and 34 normal controls for a LC-MS-based metabolomics study.Results184 metabolites were increased and 86 metabolites were decreased in the positive ion mode, and 65 metabolites were increased and 71 were decreased in the negative ion mode. Also, it was found that the unsaturated fatty acid metabolism was disordered in GDM. Ten metabolites with the most significant differences were selected for follow-up studies. Since the diagnostic specificity and sensitivity of a single differential metabolite are not definitive, we combined these metabolites to prepare a ROC curve. We found a set of metabolite combination with the highest sensitivity and specificity, which included eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, arachidonic acid, citric acid, α-ketoglutaric acid, and genistein. The area under the curves (AUC) value of those metabolites was 0.984 between the GDM and control group.ConclusionsOur results provide a direction for the mechanism of GDM research and demonstrate the feasibility of developing a diagnostic test that can distinguish between GDM and normal controls clearly. Our findings were helpful to develop novel biomarkers for precision or personalized diagnosis for GDM. In addition, we provide a critical insight into the pathological and biological mechanisms for GDM.
| S-EPMC8211500 | biostudies-literature