Tumor Endothelial Cell-Derived Extracellular Vesicles Promote Hepatocellular Carcinoma Progression Through...

The aim of this study was to determine whether the interaction of HCC cells and tumor endothelial cells (TECs) via extracellular vesicle (EV) is involved in the progression of HCC.

Five sets of matched HCC and adjacent tissues were collected from patients with primary HCC who underwent liver resections. The TECs and normal endothelial cells (NECs) were isolated with magnetic selection of CD31⁺ cells. Condition medium (CM) and EV derived from NECs and TECs were co-cultured with the human HCC cell lines. miRNA sequencing analysis was performed to characterize the miRNA profiles of EVs. Additionally, the relationships between prognosis and miRNA targeted proteins in HCC tissues were analyzed among 121 HCC patients.

Both TECs and NECs exhibited high expression levels of CD31 protein. In tube-forming assays, NECs and TECs formed round tubes characteristic of cultured endothelial cells. Functional assays revealed that TEC-derived CM and EV markedly enhanced migration and invasiveness in HCC cells, whereas NEC-derived CM and EV showed minimal effects. miR-142-3p was significantly upregulated in TECs-derived EVs, which reduced RHOBTB3 expression and promoted HCC migration and invasiveness. miR-20a-5p was significantly downregulated in TECs-derived EVs, which increased ITGB8 expression and promoted HCC migration and invasiveness. Furthermore, low RHOBTB3 and high ITGB8 expression in HCC tissues were significant risk factors for recurrence and survival in HCC patients.

TECs-derived EV accelerate HCC progression through intercellular interaction via miRNA, suggesting that TECs can be potential therapeutic target in HCC patients.