Circular RNA circSETD3 hampers cell growth, migration, and stem cell properties in bladder cancer through sponging miR-641 to upregulate PTEN

Abstract

ABSTRACT Bladder cancer (BLCA) is a common malignant urothelial cancer in the world. Although circular RNAs (circRNAs) involve in regulating BLCA progression, the role of a novel circular RNA circSETD3 in regulating BLCA pathogenesis has not been studied. The expression of circSETD3, miR-641, PTEN mRNA in BLCA tissues and cell lines were measured using RT-qPCR. The gain-of-function experiments were performed in vitro and in vivo to detect the effects of circSETD3 on cell proliferation, migration, EMT, and stemness maintenance. Besides, rescue experiments were performed to demonstrate the regulatory mechanism of circSETD3/miR-641/PTEN in BLCA cell malignant phenotypes in vitro. CircSETD3 was remarkably downregulated in the cancerous clinical tissues and cell lines, in contrast with their normal counterparts, and circSETD3 tended to be deficient in BLCA patients with larger tumor size, advanced clinical stages, positive lymph metastasis and worse prognosis. In addition, circular isoforms of circSETD3 were more resistant to RNase R+ and actinomycetes D treatment compared to their linear isoforms, and circSETD3 mainly distributed in the cytoplasm of the BLCA cells. Further gain-of-function experiments showed that circSETD3 acted as a tumor suppressor to suppress BLCA cell proliferation, migration, EMT and stemness, and the underlying mechanisms had also been elucidated. Mechanistically, circSETD3 sponged miR-641 to upregulate PTEN, resulting in the blockage of BLCA progression. Our findings indicated that circSETD3 acted as a vital tumor suppressor in BLCA via regulating the miR-641/PTEN axis.