Dataset Information

Subcellular Localization of uc.8+ as a Prognostic Biomarker in Bladder Cancer Tissue.

ABSTRACT: Non-coding RNA transcripts originating from Ultraconserved Regions (UCRs) have tissue-specific expression and play relevant roles in the pathophysiology of multiple cancer types. Among them, we recently identified and characterized the ultra-conserved-transcript-8+ (uc.8+), whose levels correlate with grading and staging of bladder cancer. Here, to validate uc.8+ as a potential biomarker in bladder cancer, we assessed its expression and subcellular localization by using tissue microarray on 73 human bladder cancer specimens. We quantified uc.8+ by in-situ hybridization and correlated its expression levels with clinical characteristics and patient survival. The analysis of subcellular localization indicated the simultaneous presence of uc.8+ in the cytoplasm and nucleus of cells from the Low-Grade group, whereas a prevalent cytoplasmic localization was observed in samples from the High-Grade group, supporting the hypothesis of uc.8+ nuclear-to-cytoplasmic translocation in most malignant tumor forms. Moreover, analysis of uc.8+ expression and subcellular localization in tumor-surrounding stroma revealed a marked down-regulation of uc.8+ levels compared to the paired (adjacent) tumor region. Finally, deep machine-learning approaches identified nucleotide sequences associated with uc.8+ localization in nucleus and/or cytoplasm, allowing to predict possible RNA binding proteins associated with uc.8+, recognizing also sequences involved in mRNA cytoplasm-translocation. Our model suggests uc.8+ subcellular localization as a potential prognostic biomarker for bladder cancer.

SUBMITTER: Terreri S

PROVIDER: S-EPMC7914980 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Subcellular Localization of uc.8+ as a Prognostic Biomarker in Bladder Cancer Tissue.

Terreri Sara S Mancinelli Sara S Ferro Matteo M Vitale Maria Concetta MC Perdonà Sisto S Castaldo Luigi L Gigantino Vincenzo V Mercadante Vincenzo V De Cecio Rossella R Aquino Gabriella G Montella Marco M Angelini Claudia C Del Prete Eugenio E Aprile Marianna M Ciaramella Angelo A Liguori Giovanna L GL Costa Valerio V Calin George A GA La Civita Evelina E Terracciano Daniela D Febbraio Ferdinando F Cimmino Amelia A

Cancers 20210208 4

Non-coding RNA transcripts originating from Ultraconserved Regions (UCRs) have tissue-specific expression and play relevant roles in the pathophysiology of multiple cancer types. Among them, we recently identified and characterized the ultra-conserved-transcript-8+ (uc.8+), whose levels correlate with grading and staging of bladder cancer. Here, to validate uc.8+ as a potential biomarker in bladder cancer, we assessed its expression and subcellular localization by using tissue microarray on 73 h ...[more]

PMID: 33567603

Similar Datasets

Project description:It is becoming increasingly clear that no single marker will have the sensitivity and specificity necessary to be used on its own for diagnosis/prognosis of tumors. Interpatient and intratumor heterogeneity provides overwhelming odds against the existence of such an ideal marker. With this in mind, our laboratory has been applying a long term systematic approach to identify multiple biomarkers that can be used for clinical purposes. As a result of these studies, we have identified and reported several candidate biomarker proteins that are deregulated in bladder cancer. Following the conceptual biomarker development phases proposed by the Early Detection Research Network, we have taken some of the most promising candidate proteins into postdiscovery validation studies, and here we report on the characterization of one such biomarker, the bladder cancer-associated protein (BLCAP), formerly termed Bc10. To characterize BLCAP protein expression and cellular localization patterns in benign bladder urothelium and urothelial carcinomas (UCs), we used two independent sets of samples from different patient cohorts: a reference set consisting of 120 bladder specimens (formalin-fixed as well as frozen biopsies) and a validation set consisting of 2,108 retrospectively collected UCs with long term clinical follow-up. We could categorize the UCs examined into four groups based on levels of expression and subcellular localization of BLCAP protein and showed that loss of BLCAP expression is associated with tumor progression. The results indicated that increased expression of this protein confers an adverse patient outcome, suggesting that categorization of staining patterns for this protein may have prognostic value. Finally, we applied a combinatorial two-marker discriminator using BLCAP and adipocyte-type fatty acid-binding protein, another UC biomarker previously reported by us, and found that the combination of the two markers correlated more closely with grade and/or stage of disease than the individual markers. The implications of these results in biomarker discovery are discussed.

Project description:BackgroundThe objective of this study was to evaluate Octamer-binding transcription factor 4 (Oct-4), neutrophil to lymphocyte ratio (NLR) and body mass index (BMI) as independent prognostic biomarkers for prediction of urinary bladder cancer (UBC) outcomes. With the advancement in prognostic biomarker discovery, tumor recurrence is difficult to accurately predict in UBC. UBC is costly to treat due to the requirement of frequent invasive follow-up sessions. Therefore, it is of utmost importance to evaluate good prognostic biomarkers for UBC surveillance.MethodsWe studied 39 UBC tissue samples. Oct-4 protein expression was evaluated semiquantitatively by immunohistochemistry (IHC). Complete blood count data and body weight as well as the height of the patients were retrieved and recorded before the date of the first transurethral resection of bladder tumor (TURBT). The follow-up period was 48 months for recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS).ResultsOct-4 expression profile was found to be significantly associated with gender (p = 0.028), tumor grade (p = 0.038), tumor stage (p = 0.003), lymph node status (p = 0.029), recurrence (p = 0.004), progression (p = 0.011), and treatment modality (p = 0.016). Tumor grade and progression were found significant with NLR values (tumor grade, p = 0.006; progression, p = 0.038) and BMI (tumor grade, p = 0.036; progression, p = 0.014). Moreover, BMI was also significantly associated with UBC recurrence (p = 0.014). Kaplan-Meier survival analysis showed poor prognosis with both high Oct-4 expression (RFS, p = 0.001; PFS, p = 0.004; OS, p = 0.014) and high NLR values (RFS, p = 0.049; PFS, p = 0.004; OS, p = 0.005). Patients with high BMI too had poor RFS (p = 0.025) and poor PFS (p = 0.032). Furthermore, multivariate Cox regression analysis, indicated Oct-4 as an independent prognostic biomarker for RFS (HR = 0.240, 95% CI, 0.072-0.804, p = 0.021).ConclusionsWe conclude that the expression profile of Oct-4 will be beneficial in prediction of UBC recurrence, and could have profound implications on the development of new therapeutic targets for UBC treatment.

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.

Dataset Information

Subcellular Localization of uc.8+ as a Prognostic Biomarker in Bladder Cancer Tissue.

Publications

Subcellular Localization of uc.8+ as a Prognostic Biomarker in Bladder Cancer Tissue.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets