Abstract
BackgroundBladder cancer (BLCA) is one of the most common malignancies worldwide. One of the main reasons for the unsatisfactory management of BLCA is the complex molecular biological mechanism. Annexin A1 (ANXA1), a Ca2+-regulated phospholipid-binding protein, has been demonstrated to be implicated in the progression and prognosis of many cancers. However, the expression pattern, biological function and mechanism of ANXA1 in BLCA remain unclear.MethodsThe clinical relevance of ANXA1 in BLCA was investigated by bioinformatics analysis based on TCGA and GEO datasets. Immunohistochemical (IHC) analysis was performed to detect the expression of ANXA1 in BLCA tissues, and the relationships between ANXA1 and clinical parameters were analyzed. In vitro and in vivo experiments were conducted to study the biological functions of ANXA1 in BLCA. Finally, the potential mechanism of ANXA1 in BLCA was explored by bioinformatics analysis and verified by in vitro and in vivo experiments.ResultsBioinformatics and IHC analyses indicated that a high expression level of ANXA1 was strongly associated with the progression and poor prognosis of patients with BLCA. Functional studies demonstrated that ANXA1 silencing inhibited the proliferation, migration, invasion and epithelial–mesenchymal transition (EMT) of BLCA cells in vitro, and suppressed the growth of xenografted bladder tumors in vivo. Mechanistically, loss of ANXA1 decreased the expression and phosphorylation level of EGFR and the activation of downstream signaling pathways. In addition, knockdown of ANXA1 accelerated ubiquitination and degradation of P-EGFR to downregulate the activation of EGFR signaling.ConclusionsThese findings indicate that ANXA1 is a reliable clinical predictor for the prognosis of BLCA and promotes proliferation and migration by activating EGFR signaling in BLCA. Therefore, ANXA1 may be a promising biomarker for the prognosis of patients with BLCA, thus shedding light on precise and personalized therapy for BLCA in the future.
Highlights
Bladder cancer (BLCA) is one of the most common malignancies worldwide, with approximately 5490,000 new cases and 200,000 deaths per year, and is generally classified into two major groups based upon depth of invasion: non-muscle-invasive bladder cancerLi et al Cancer Cell International (2022) 22:7(NMIBC) and muscle-invasive bladder cancer (MIBC) [1, 2]
According to the optimum cutoff threshold calculated by X-tile software, the samples of the The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were divided into high Annexin A1 (ANXA1) (TCGA: n = 200, GEO: n = 18) and low ANXA1 (TCGA: n = 207, GEO: n = 147) groups
Gene Set Enrichment Analysis (GSEA) analysis demonstrated that the gene set relevant to bladder cancer was enriched in TCGA samples with high ANXA1 expression (Fig. 1K)
Summary
Bladder cancer (BLCA) is one of the most common malignancies worldwide, with approximately 5490,000 new cases and 200,000 deaths per year, and is generally classified into two major groups based upon depth of invasion: non-muscle-invasive bladder cancer. (NMIBC) and muscle-invasive bladder cancer (MIBC) [1, 2]. 80% of bladder cancer patients are diagnosed with NMIBC, and the remaining 20% present with MIBC [2]. Antibody–drug conjugates, target therapies, and immunotherapy have been introduced and shown to be beneficial for some bladder cancer patients, improving the prognosis of advanced BLCA patients still faces severe challenges [7,8,9]. The expression pattern, biological function and mechanism of ANXA1 in BLCA remain unclear
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