CircRNA ATF6 suppresses bladder cancer cell proliferation and migration via miR-146a-5p/FLNA axis

Background: Bladder Cancer (BCa) is the most common malignancy with increasing morbidity and mortality. Circular RNA (circRNA) ATF6 level was downregulated in BCa after GSE92675 CircRNA microarray dataset was analyzed using GEO2R. However, its function and mechanism in BCa remain largely unknown.

Methods: GEO2R and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were used to measure levels of circRNA ATF6, microRNA-146a-5p (miR-146a-5p), and filamin A (FLNA). CircRNA ATF6 stability was assessed by actinomycin D and RNase R assays, while circRNA ATF6 cellular localization was examined by FISH experiments in T24 cells. Cell counting kit-8 (CCK-8), colony formation, wound-healing, and transwell assays were used to study circRNA ATF6's function in growth, motility, and invasion. By examining luciferase, starBase, RNA pull-down, and RNA immunoprecipitation (RIP) experiments, we anticipated and confirmed miR-146a-5p interactions with circRNA ATF6, as well as miR-146a-5p interactions with FLNA. On tumor-bearing mice, in vivo experiments were conducted.

Results: MiR-146a-5p expression in Bca was elevated, while circRNA ATF6 and FLNA were downregulated. CircRNA ATF6 showed better stability in BCa cells, with its expression primarily in the cytoplasm. Upregulating circRNA ATF6 lowered BCa cell viability, colony numbers, and invasion numbers, but broadened their migratory pattern. MiR-146a-5p was directly sponged up by circRNA ATF6, which also detrimentally affected miR-146a-5p levels in BCa. MiR-146a-5p reduced BCa FLNA expression by targeting FLNA. FLNA silencing abolished circRNA ATF6's mitigating function in BCa cell proliferation, motility, and invasion. In vivo, overexpression of circRNA ATF6 significantly reduced tumor volume and weight.

Conclusion: CircRNA ATF6 suppresses BCa cell growth, migration and invasion through the miR-146a-5p/FLNA axis.

Bladder cancer; CircRNA ATF6; FLNA; MiR-146a-5p; Migration; Proliferation.