MiR-375 in CAFs-Derived EVs Promotes HCC Progression via Regulating RASA1 and May Potentially Serve as a Biomarker for HCC.

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment play an important role in cancer initiation and progression through mediating crosstalk between CAFs and cancer cells. In our study, we unveiled that CAFs-derived extracellular vesicles (EVs) could deliver miR-375 to endothelial cells (EC) and further contribute to tumor angiogenesis by regulating Ras GTPase Activating Protein 1 (RASA1) in hepatocellular carcinoma (HCC). We also found that HCC patients with more advanced disease showed higher levels of miR-375 in plasma EVs, which were preferentially expressed in the EVs of CAFs. These data provided direct evidence supporting the pivotal role of the tumor suppressor miR-375, which is selectively sorted into CAF-derived EVs, in promoting angiogenesis during HCC progression and revealed that genetically modified CAF-derived EVs may provide a potential therapeutic strategy for HCC. Furthermore, our study indicated that miR-375 in plasma EVs could serve as a potential predictive and prognostic biomarker in HCC patients.