Exosomal ETV4 Derived From M2 Macrophages Induces Growth, Glycolysis and Stemness in Hepatocellular Carcinoma by UpRegulating SULT2B1 Expression.

Abstract

Background: M2 macrophage-derived exosomes have been identified to modulate hepatocellular carcinoma (HCC) progression. E-twenty-six (ETS) variant transcription factor 4 (ETV4) shows protumoral effects in HCC. Here, we aimed to probe whether ETV4 performed oncogenic effects on HCC by macrophage-derived exosomes and its associated mechanism.

Methods: Exosomes were isolated from macrophages and co-cultured with HCC cells. qRT-PCR and western blotting were utilised for the detection of mRNA and protein. Cell survival was evaluated using EdU assay and flow cytometry. Glycolysis was determined by measuring the glucose uptake, lactate production, and ATP levels. Cell stemness was assessed by sphere formation and flow cytometry. The interaction between ETV4 and SULT2B1 (sulfotransferase family 2B member 1) was determined by a dual-luciferase reporter and chromatin immunoprecipitation assays. In vivo assay was performed by establishing mouse xenograft models.

Results: ETV4 was highly expressed in the exosomes of M2 macrophages and could be internalised by HCC cells. ETV4 derived from M2 macrophage exosomes promoted HCC cell proliferation, glycolysis and stemness in vitro, and enhanced HCC growth in nude mice. Mechanistically, ETV4 interacted with SULT2B1 and promoted it transcription. SULT2B1 silencing suppressed HCC cell proliferation, glycolysis and stemness. In addition, exosomal ETV4 derived from M2 macrophage performed its effects by modulating SULT2B1.

Conclusion: ETV4 derived from M2 macrophage exosomes promoted HCC cell proliferation, glycolysis and stemness by interacting with SULT2B1, suggesting a novel insight into developing exosome-based therapy for HCC.