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Upregulation of RAC3 in bladder cancer predicts adverse clinical outcome and increased tumor immune response

ABSTRACT: The relationship between RAC3 expression and clinical outcome in bladder cancer (BLCA) was uncertain. In this study, the expression level of RAC3 in BLCA and its clinical outcome were analyzed through various independent public databases. The mRNA expression level of RAC3 in BLCA and normal bladder was evaluated from the Gene Expression Omnibus (GEO), Oncomine, and The Cancer Genome Atlas (TCGA) database. The protein expression of RAC3 in BLCA and normal bladder was investigated from immunohistochemical images through the Human Protein Atlas (HPA) database. Next, gene tumor immune analyses were performed. Furthermore, gene set enrichment analysis (GESA) by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment (KEGG) for RAC3 and its co-expressed genes were performed. Then, GESA was also performed to validate the KEGG pathways by the different expression of RAC3 in BLCA. The results indicated that, compared with normal bladder, the mRNA and protein expression of RAC3 in BLCA were both significantly higher than those of normal bladder tissues (P<0.05). The tumor immune analyses indicated RAC3 was associated with microsatellite instability, tumor mutational burden, tumor immune microenvironment, and immune cell infiltration level evaluation (P<0.05). The survival analysis result demonstrated that upregulation of RAC3 was associated with adverse survival in BLCA (P<0.05). Taken together, these findings suggest that RAC3 may be associated with adverse clinical outcome and increased tumor immune response in BLCA, and may be a prognostic and immunotherapy marker for BLCA.

SUBMITTER: Ou-Yang S

PROVIDER: S-EPMC7791394 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:Background: Bladder cancer (BC) is a leading cause of death from malignancy, with significant heterogeneity in the immunotherapeutic responsiveness of advanced status. Pyroptosis, a newly discovered inflammatory programmed cell death, is confirmed to play an indispensable role in tumorigenesis and anti-tumor activity. However, the effect of pyroptosis on the tumor-immune landscape remodeling and immunotherapy in BC remains elusive. Methods: We comprehensively evaluated the mRNA expression and genomic alterations of 33 pyroptosis-related genes (PRGs) in BC and evaluated the patterns of pyroptosis in publicly available BC datasets. An unsupervised clustering method was used to classify patients into distinct patterns. Then, we established a pyroptosis-related signature score (PS-score) model to quantify the pyroptosis-related patterns of individual BC patients using principal component analysis. Furthermore, we correlated the patterns with the immune landscape and response efficacy of immunotherapy. Results: Two pyroptosis-related patterns were identified in BC, and distinct patterns showed various immune characteristics. Patterns with a high expression level of PRGs exhibited a survival advantage and showed higher infiltration of cytotoxic lymphocytes. Tumors with a low PS-score were characterized by high tumor-infiltrating lymphocytes and considered "hot." Further analysis revealed that the PS-score was an independent prognostic factor and could predict the response to immunotherapy for patients with advanced BC. We found a significant positive association between AHNAK2, AHNAK nucleoprotein 2, expression, and PS-score. Functional assays showed that AHNAK2 knockdown was correlated with attenuated invasive ability. Conclusion: This work comprehensively demonstrated the potential function of pyroptosis-related patterns in the bladder tumor-immune landscape and identified their therapeutic liability in immunotherapy. Our study enhanced our understanding of the immune landscape and provided a new approach toward more effective immunotherapy strategies.

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Upregulation of RAC3 in bladder cancer predicts adverse clinical outcome and increased tumor immune response

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