Circular RNA Ubiquitin-associated Protein 2 Silencing Suppresses Bladder Cancer Progression by Downregulating DNA Topoisomerase 2-alpha Through Sponging miR-496.

Background: Circular RNAs (circRNAs) have been uncovered to be implicated in the malignant development of bladder cancer (BC). Objective: Herein, this work aimed to investigate the role and mechanism of circRNA ubiquitin-associated protein 2 (circUBAP2) in BC progression. Design setting and participants: Quantitative real-time polymerase chain reaction and Western blotting were used for the detection of genes and proteins. Outcome measurements and statistical analysis: In vitro functional experiments were conducted using colony formation, 5-ethynyl-2'-deoxyuridine (EdU), Transwell, wound healing, and flow cytometry assays, respectively. A glycolysis analysis was conducted by assessing glucose uptake and lactate production. A murine xenograft model was established to perform in vivo experiments. The binding interaction between miR-496 and circUBAP2 or DNA topoisomerase 2-alpha (TOP2A) was verified using a dual-luciferase reporter assay. Results and limitations: CircUBAP2 was highly expressed in BC patients, and high circUBAP2 expression showed a shorter survival rate. Functionally, knockdown of circUBAP2 could suppress BC cell growth, migration, invasion, and aerobic glycolysis in vitro, as well as impede BC growth in nude mice. Mechanistically, circUBAP2 acted as a sponge for miR-496, which targeted TOP2A. Moreover, circUBAP2 could indirectly regulate TOP2A expression through sequestering miR-496. Furthermore, a series of rescue experiments showed that miR-496 inhibition reversed the anticancer action of circUBAP2 knockdown on BC cells. Moreover, miR-496 could attenuate BC cell malignant phenotypes and aerobic glycolysis, which were abolished by TOP2A overexpression. Conclusions: Silencing of circUBAP2 could suppress BC growth, invasion, migration, and aerobic glycolysis by the miR-496/TOP2A axis, suggesting a promising target for the molecular targeted therapies of BC. Patient summary: Circular RNA ubiquitin-associated protein 2 (circUBAP2) was found to be associated with poor prognosis in bladder cancer (BC). Knockdown of circUBAP2 might suppress BC growth, invasion, migration, and aerobic glycolysis, indicating that it may be a new target for the development of molecular targeted therapy for BC.