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

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.

Higher Expression of Annexin A2 in Metastatic Bladder Urothelial Carcinoma Promotes Migration and Invasion

“…Thus, it is essential to identify molecular markers to detect bladder cancer early before cancer cells become invasive and metastatic. Annexins display different expression patterns in bladder cancer and play an essential role in the pathogenesis by triggering various downstream signaling pathways and functional regulatory effects [ 19 , 20 , 43 , 44 , 45 , 46 , 47 , 48 ]. Increasing evidence indicates that AnxA2 is upregulated in several types of human cancer [ 13 , 17 , 21 , 22 , 24 , 26 , 27 , 28 , 29 ].…”

High expression of the ANXA3 gene promotes immune infiltration and improves tumor prognosis in ovarian serous carcinoma using bioinformatics analyses

“…To date, ANXA3 has been found to not only maintain genomic integrity and facilitate cell proliferation and differentiation but also contributes to tumor initiation and growth. We synthesized the relevant literature and found that that ANXA3 expression was dysregulated in a large number of tumor populations, such as bladder urothelial carcinoma ( 23 ), BRCA ( 17 ), CHOL ( 16 ), COAD ( 24 ), esophageal carcinoma ( 25 ), head and neck squamous cell carcinoma ( 26 ), kidney chromophobe ( 27 ), kidney renal papillary cell carcinoma ( 28 ), hepatocellular carcinoma ( 29 ), LUAD ( 30 ), LUSC ( 31 ), pancreatic adenocarcinoma ( 32 ), PRAD ( 33 ), READ ( 34 ), stomach adenocarcinoma ( 25 ), thyroid carcinoma ( 35 ), and uterine corpus endometrial carcinoma ( 13 ). In this study, an increased ANXA3 expression was associated with a favorable prognosis, suggesting that ANXA3 might play a pivotal role in decreasing cancer risk in patients with OV.…”

Pathobiological functions and clinical implications of annexin dysregulation in human cancers

“…In bladder cancer, ANXA11 expression levels were decreased in tumor tissue compared to the normal counterpart, and together with other annexins, serves to identify luminal-subtype bladder tumors ( Wu et al, 2021 ). Moreover, high ANXA11 levels were associated with a higher overall survival in bladder cancer patients ( Yao et al, 2022 ), further supporting an oncosuppressor role in this malignancy.…”