CircETFA upregulates CCL5 by sponging miR-612 and recruiting EIF4A3 to promote hepatocellular carcinoma

As a kind of malignant tumors, hepatocellular carcinoma (HCC) has been studied continuously, but the mechanisms are not well understood. Circular RNAs (circRNAs) are widespread in eukaryotes and play an important role in the growth of organisms and in the occurrence of diseases. The role of circRNAs in HCC remains to be further explored. In this study, CircRNA microarray analysis was used to assess the plasma from HCC patients and healthy controls and to identify circRNAs involved in HCC tumorigenesis. CircETFA was overexpressed in HCC tissues, plasma, and cells. Clinicopathological data revealed that abnormally high circETFA expression was associated with a poor prognosis. In function, circETFA promotes the malignant phenotype of HCC cells in vivo and in vitro, inhibits cycle arrest, and decreases the proportion of apoptotic cells. In mechanism, it can upregulate C-C motif chemokine ligand 5 (CCL5) in HCC cells, thereby regulating the phosphoinositide 3-kinase (PI3K)/Akt pathway and other key downstream effectors (e.g., FoxO6). Furthermore, circETFA prolonged the half-life of CCL5 mRNA by recruiting the eukaryotic initiation factor 4A3 (EIF4A3) and acted as a sponge of hsa-miR-612 to suppress the silencing effect of hsa-miR-612 on CCL5. In conclusion, CircETFA can increase the expression of CCL5 to promote the progression of HCC by sponging hsa-mir-612 and recruiting EIF4A3, and is promising as a novel biomarker and therapeutic target.