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

SIMPLE SUMMARY: Bladder urothelial carcinoma (BLCA) arises from basal cells that develop dysplasia and carcinoma in situ and, if unchecked, progress to invasion and metastases. Major players underlying the molecular mechanisms of invasive and metastatic BLCA are yet to be determined. Annexin A2 (AnxA2), a Ca(++)-dependent phospholipid-binding protein, is overexpressed in various cancers and facilitates cell migration and invasion. This study established a correlation between AnxA2 and BLCA using existing BLCA data from the Cancer Genome Atlas (TCGA). In addition, we determined its role in the proliferation, migration, and invasion of metastatic bladder cancer cells. ABSTRACT: In this study, we aim to evaluate the significance of AnxA2 in BLCA and establish its metastatic role in bladder cancer cells. Analysis of TCGA data showed that AnxA2 mRNA expression was significantly higher in BLCA tumors than in normal bladder tissues. High mRNA expression of AnxA2 in BLCA was significantly associated with high pathological grades and stages, non-papillary tumor histology, and poor overall survival (OS), progression-free survival (PFS), and diseases specific survival (DSS). Similarly, we found that AnxA2 expression was higher in bladder cancer cells derived from high-grade metastatic carcinoma than in cells derived from low-grade urothelial carcinoma. AnxA2 expression significantly mobilized to the surface of highly metastatic bladder cancer cells compared to cells derived from low-grade tumors and associated with high plasmin generation and AnxA2 secretion. In addition, the downregulation of AnxA2 cells significantly inhibited the proliferation, migration, and invasion in bladder cancer along with the reduction in proangiogenic factors and cytokines such as PDGF-BB, ANGPT1, ANGPT2, Tie-2, bFGF, GRO, IL-6, IL-8, and MMP-9. These findings suggest that AnxA2 could be a promising biomarker and therapeutic target for high-grade BLCA.