Exosomal circRNA_0023016 suppresses hepatocellular carcinoma progression by regulating the EIF4A3/RNF113A/CXCR4 axis in endothelial cells.

The invasion and metastasis of hepatocellular carcinoma (HCC) have been confirmed to be primarily associated with angiogenesis, and the underlying mechanisms remain elusive. In this study, we analyzed the GSE121714 database to identify circRNA_0023016, which is closely related to angiogenesis but has not been studied, as our target RNA for further investigation. The expression of circRNA_0023016 was identified to be downregulated in high invasion HCC cell lines and patients' tissues as well as serum exosomes. Inhibition of exosomal circRNA_0023016 downregulated eukaryotic translation initiation factor 4A3 (EIF4A3) and ring finger protein 113 A (RNF113A), while elevating C-X-C chemokine receptor type 4 (CXCR4) in human umbilical vein endothelial cells (HUVECs). EIF4A3 was found to be bound to circRNA_0023016 at RNA-protein level and to interact with RNF113A. The inhibition of RNF113A prevented the Cullin-RING E3 ligases (CRLs)-mediated K48-linked ubiquitination and proteasomal degradation of CXCR4. Furthermore, the RNA level of circRNA_0023016 and the protein expression of EIF4A3/RNF113A/CXCR4 axis in angiogenic endothelial cells, which were isolated from mouse HCC tissues via flow sorting, were detected to minimize potential interference from other cells. Overall, a new exosomal circRNA_0023016/EIF4A3/RNF113A/CXCR4 axis was identified in HCC. Exosomal circRNA_0023016 may serve as a potential therapeutic target, particularly for high invasion HCC.