Evaluating the regulatory network of EV-derived miRNA in the microenvironment of hepatocellular carcinoma

The progression of hepatocellular carcinoma (HCC) is influenced by the tumor microenvironment (TME) profoundly, where extracellular vesicle (EV)-derived microRNA (miRNA) plays a pivotal regulatory role. Despite growing interest, the mechanisms of intercellular communication in HCC mediated by EV-derived miRNA remain poorly understood. Four individual scRNA-seq datasets were merged and analyzed using miRTalk to investigate the roles of EV-derived miRNA-target interactions (MiTIs) in TME of HCC. Signaling pathway predictions were also performed using miRTalk. Survival and cox proportional hazards analysis were also conducted based on bulk transcriptomic data from TCGA-LIHC cohort. A total of 208 miRNA-target gene pairs were found to be significantly associated with prognosis, 51 pairs were classified as tumor-suppressive, and 157 pairs were identified as tumor-progressive. Hsa-miR-1539 was predicted to be transferred from T or NK cells and to regulate ETV5 in epithelial cells. Epithelial cells-derived hsa-miR-3180-5p in the EVs was found to play a key role in regulating tumor-related genes including AGO3 and FSCN1 in fibroblasts and endothelial cells respectively, also regulating ALG8, ARL5B, EIF6, FADS1, KIF5B, MOB3A, MTRF1L, PTPRF, and RPF2 to form a pro-tumor gene network. This study systematically maps EV-mediated miRNA regulatory networks in HCC TME. We nominate hsa-miR-3180-5p as a potential central regulator of oncogenic networks, offering new insights into HCC progression and potential therapeutic targets. These findings provide a foundation for future research into EV-based interventions in HCC management.