Identification and Validation of an Annexin-Related Prognostic Signature and Therapeutic Targets for Bladder Cancer: Integrative Analysis

SIMPLE SUMMARY: Identification of new prognostic biomarkers and therapeutic targets could be essential ways to improve the outcome of bladder cancer (BC) patients. In this study, we comprehensively analyzed the mRNA expression and prognosis of Annexin family members (ANXA1-11, 13) in BC through public analysis tools, including Oncomine, GEPIA2 and our in-house OSblca web server, and found that several Annexins were aberrantly expressed and associated with prognosis in BC. Then, we constructed and validated an Annexin-related prognostic signature (ARPS) in four individual BC cohorts through LASSO and COX regression, indicating that ARPS was an independent prognostic factor for BC. Briefly, our study was to determine the clinical significance of Annexins and provided a potential prognostic model and potential therapeutic targets for BC. ABSTRACT: Abnormal expression and dysfunction of Annexins (ANXA1-11, 13) have been widely found in several types of cancer. However, the expression pattern and prognostic value of Annexins in bladder cancer (BC) are currently still unknown. In this study, survival analysis by our in-house OSblca web server revealed that high ANXA1/2/3/5/6 expression was significantly associated with poor overall survival (OS) in BC patients, while higher ANXA11 was associated with increased OS. Through Oncomine and GEPIA2 database analysis, we found that ANXA2/3/4/13 were up-regulated, whereas ANXA1/5/6 were down-regulated in BC compared with normal bladder tissues. Further LASSO analysis built an Annexin-Related Prognostic Signature (ARPS, including four members ANXA1/5/6/10) in the TCGA BC cohort and validated it in three independent GEO BC cohorts (GSE31684, GSE32548, GSE48075). Multivariate COX analysis demonstrated that ARPS is an independent prognostic signature for BC. Moreover, GSEA results showed that immune-related pathways, such as epithelial–mesenchymal transition and IL6/JAK/STAT3 signaling were enriched in the high ARPS risk groups, while the low ARPS risk group mainly regulated metabolism-related processes, such as adipogenesis and bile acid metabolism. In conclusion, our study comprehensively analyzed the mRNA expression and prognosis of Annexin family members in BC, constructed an Annexin-related prognostic signature using LASSO and COX regression, and validated it in four independent BC cohorts, which might help to improve clinical outcomes of BC patients, offer insights into the underlying molecular mechanisms of BC development and suggest potential therapeutic targets for BC.