Dataset Information

Gasdermin D: A potential mediator and prognostic marker of bladder cancer.

ABSTRACT: Background: Bladder cancer is considered one of the commonest widespread cancers, its presentation ranges from non-muscle invasive form to being muscle-invasive. The gasdermin family of proteins consists of six proteins. Members of gasdermin family are involved in pyroptosis; which is considered as type of inflammatory apoptosis via participation of gasdermin D and inflammatory caspases. Purpose: The goal of this research was to look into the potential involvement of gasdermin D in pathogenesis of bladder cancer, In addition, to investigate its potential role as a prognostic marker of bladder cancer. Methods: Gasdermin D gene and protein expression was examined in fresh frozen 80 bladder cancer specimens (30 NMIBC, and 50 MIBC) and the matching 80 control tissue samples utilizing real-time polymerase chain reaction and western blotting. Furthermore, the immunoreactivity of gasdermin D protein was also detected by immunohistochemistry. Results: Gasdermin D gene and protein expression showed a highly significant difference between the control and the two bladder cancer groups (p < 0.001), as demonstrated by real-time PCR, western blotting and immunohistochemistry. Cox proportional hazards regression models showed that lower gasdermin D gene expression in cancer patients (≤1.58-fold), and younger age (≤53 years) were linked with a higher risk of local tumor recurrence. Moreover, higher gasdermin D gene expression (>2.18-fold), and lymph nodes' involvement were associated with an increased mortality. Conclusion: Gasdermin D is involved in the pathogenesis of bladder cancer and muscle invasion, in addition, tissue gasdermin D expression may be used as useful tool to predict local tumor recurrence.

SUBMITTER: El-Gamal R

PROVIDER: S-EPMC9474890 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Gasdermin D: A potential mediator and prognostic marker of bladder cancer.

El-Gamal Randa R Abdelrahim Mona M El-Sherbiny Mohamed M Enan Eman T ET El-Nablaway Mohammad M

Frontiers in molecular biosciences 20220901

<b>Background:</b> Bladder cancer is considered one of the commonest widespread cancers, its presentation ranges from non-muscle invasive form to being muscle-invasive. The gasdermin family of proteins consists of six proteins. Members of gasdermin family are involved in pyroptosis; which is considered as type of inflammatory apoptosis via participation of gasdermin D and inflammatory caspases. <b>Purpose:</b> The goal of this research was to look into the potential involvement of gasdermin D in ...[more]

PMID: 36120543

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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:BackgroundOne of the most common malignant tumors of the urinary system is muscle-invasive bladder cancer (MIBC). With the increased use of immunotherapy, its importance in the field of cancer is becoming abundantly evident. This study classifies MIBC according to GSVA score from the perspective of the GSEA immune gene set.MethodsThis study integrated the sequencing and clinical data of MIBC patients in TCGA and GEO databases, then scored the data using the GSVA algorithm, the CNMF algorithm was implemented to divide the subtypes of GEO and TCGA datasets, respectively, and finally screened and determined the key pathways in combination with clinical data. Simultaneously, LASSO Cox regression model was constructed based on key pathway genes to assess the model's predictive ability (ROC) and describe the immune landscape differences between high- and low-risk groups; key genes were further analyzed and verified in patient tissues.Results404 TCGA and 297 GEO datasets were divided into C1-3 groups (TCGA-C1:120/C2:152/C3:132; GEO- C1:112/C2:101/C3:84), of which TCGA-C2 (n = 152) subtype and GEO-C1 (n = 112) subtype had the worst prognosis. LASSO Cox regression model with ROC (train set = 0.718, test set = 0.667) could be constructed. When combined with the Cancer Immunome Atlas database, it was found that patients with high-risk scores were more sensitive to PD-1 inhibitor and PD-1 inhibitor combined with CTLA-4. NXPH4, as a key gene, plays a role in MIBC with tissue validation results show that nxph4 is highly expressed in tumor.ConclusionThe immune gene score of MIBC data in TCGA and GEO databases was successfully evaluated using GSVA in this research. The lasso Cox expression model was successfully constructed by screening immune genes, the high-risk group had a worse prognosis and higher sensitivity to immunotherapy, PD-1 inhibitors or PD-1 combined with CTLA-4 inhibitors can be preferentially used in high-risk patients who are sensitive to immunotherapy, and NXPH4 may be a molecular target to adjust the effect of immunotherapy.

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Gasdermin D: A potential mediator and prognostic marker of bladder cancer.

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Gasdermin D: A potential mediator and prognostic marker of bladder cancer.

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