Hsa_circ_0000520 suppresses vasculogenic mimicry formation and metastasis in bladder cancer through Lin28a/PTEN/PI3K signaling.

Abstract

Background: Vasculogenic mimicry (VM) is a potential cause of resistance to antiangiogenic therapy and is closely related to the malignant progression of tumors. It has been shown that noncoding RNAs play an important role in the formation of VM in malignant tumors. However, the role of circRNAs in VM of bladder cancer and the regulatory mechanisms are unclear.

Methods: Firstly, hsa_circ_0000520 was identified to have circular character by Sanger sequencing and Rnase R assays. Secondly, the potential clinical value of hsa_circ_0000520 was explored by quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH) of clinical specimens. Thirdly, the role of hsa_circ_0000520 in bladder cancer invasion, migration, and VM formation was examined by in vivo and in vitro experiments. Finally, the regulatory mechanisms of hsa_circ_0000520 in the malignant progression of bladder cancer were elucidated by RNA binding protein immunoprecipitation (RIP), RNA pulldown, co-immunoprecipitation (co-IP), qRT-PCR, Western blot (WB), and fluorescence co-localization.

Results: Hsa_circ_0000520 was characterized as a circular RNA and was lowly expressed in bladder cancer compared with the paracancer. Bladder cancer patients with high expression of hsa_circ_0000520 had better survival prognosis. Functionally, hsa_circ_0000520 inhibited bladder cancer invasion, migration, and VM formation. Mechanistically, hsa_circ_0000520 acted as a scaffold to promote binding of UBE2V1/UBC13 to Lin28a, further promoting the ubiquitous degradation of Lin28a, improving PTEN mRNA stability, and inhibiting the phosphorylation of the PI3K/AKT pathway. The formation of hsa_circ_0000520 in bladder cancer was regulated by RNA binding protein QKI.

Conclusions: Hsa_circ_0000520 inhibits metastasis and VM formation in bladder cancer and is a potential target for bladder cancer diagnosis and treatment.