Hepatocellular carcinoma cell-derived extracellular vesicles encapsulated microRNA-584-5p facilitates angiogenesis through PCK1-mediated nuclear factor E2-related factor 2 signaling pathway

Abstract

Hepatocellular carcinoma (HCC) is a fatal disease characterized by poor liver function with increasing morbidity and poor prognosis. Extracellular vesicles, released by different cells, have been associated with HCC development. Nevertheless, the mechanisms beyond extracellular vesicles in HCC remain uncharacterized. Therefore, the current study aimed to clarify the mechanism of pro-angiogenic microRNA-584-5p in hepatocellular carcinoma. Our results showed that miR-584-5p was highly-expressed in both cancer cells (Hep3B) and their extracellular vesicles. Hep3B and extracellular vesicles were then respectively co-cultured with human vascular endothelial cell line (Ea.hy926), and they both accelerated Ea.hy926 proliferation and migration. Ea.hy926 cells could internalize extracellular vesicles carrying microRNA-584-5p. Of note, microRNA-584-5p could bind to phosphoenolpyruvate carboxykinase 1 to promote nuclear factor E2-related factor 2. Moreover, silencing microRNA-584-5p was found to decline microvessel density, vascular endothelial growth factor A, and tumor growth in vivo and in vitro. Taken altogether, our findings demonstrated that extracellular vesicles-derived microRNA-584-5p promotes angiogenesis by inhibiting PCK1 -mediating NRF2 activation, which highlights the theoretical basis for potential treatments for HCC.

Keywords: Angiogenesis; Extracellular vesicle; Hepatocellular carcinoma; Nuclear factor E2-related factor 2; Phosphoenolpyruvate carboxykinase 1; Vascular endothelial growth factor A; microRNA-584-5p.