Hepatic stellate cell exosome-derived circWDR25 promotes the progression of hepatocellular carcinoma <i>via</i> the miRNA-4474-3P-ALOX-15 and EMT axes

Recently, the emerging role of circular RNAs (circRNAs) in tumor development and progression has been a topic of great interest. Nevertheless, the effects of hepatic stellate cell (HSC)-derived exosomes in hepatocellular carcinoma (HCC) remain unclear. Here, we aim to explore the potential effect of HSC exosome-derived circWDR25 on the aggressiveness of HCC. Firstly, a microarray analysis of circRNAs was performed to profile and identify the differentially expressed circRNAs derived from HSC exosomes activated by HCC cells. Subsequently, the roles of circWDR25 in HCC tumor growth and aggressiveness were confirmed through in vitro and in vivo functional experiments. Moreover, RNA pull-down, dual-luciferase reporter assays, and fluorescent in situ hybridization (FISH) were performed to determine interactions in the circWDR25-miR-4474-3p-ALOX15 loop. Immunohistochemical analysis was also performed on a microarray of HCC tissues and peritumoral tissues. We found that overexpressed peritumoral circWDR25 was associated with survival and recurrence in patients with HCC and promoted the progression of HCC cells both in vitro and in vivo. Mechanistically, both exogenous and HSC exosomal-derived circWDR25 regulated the expression of ALOX15 by sponging miR-4474-3p and ultimately inducing an epithelial-to-mesenchymal transition (EMT) in HCC cells. Moreover, exogenous and HSC exosomal-derived circWDR25 promoted the expression of CTLA-4 in HSCs and PD-L1 in HCC cells. In conclusion, circWDR25 facilitated HCC cell proliferation and invasion via the circWDR25/miR-4474-3p/ALOX15 and EMT axes and it promoted the expression of CTLA-4 in HSCs and PD-L1 in HCC cells, thus providing insights into the mechanism of tumor aggressiveness mediated by HSC-derived exosomal circWDR25.