Xu Qiaodong, Chen Xinyue, Ma Zhiyan, Zhong Haibin, Feng Gengren, Gu Songgang
Department of Hepatopancreatobiliary Surgery, Cancer Hospital of Shantou University Medical College, Shantou City, Guangdong, China.
Liver Int. 2025 Apr;45(4):e16197. doi: 10.1111/liv.16197. Epub 2024 Dec 6.
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.
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.
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.
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.
已证实M2巨噬细胞衍生的外泌体可调节肝细胞癌（HCC）的进展。E26（ETS）变异转录因子4（ETV4）在HCC中具有促肿瘤作用。在此，我们旨在探究ETV4是否通过巨噬细胞衍生的外泌体对HCC发挥致癌作用及其相关机制。
从巨噬细胞中分离出外泌体，并与HCC细胞共培养。采用qRT-PCR和蛋白质印迹法检测mRNA和蛋白质。使用EdU检测法和流式细胞术评估细胞存活率。通过测量葡萄糖摄取、乳酸生成和ATP水平来测定糖酵解。通过成球实验和流式细胞术评估细胞干性。通过双荧光素酶报告基因和染色质免疫沉淀实验确定ETV4与SULT2B1（磺基转移酶家族2B成员1）之间的相互作用。通过建立小鼠异种移植模型进行体内实验。
ETV4在M2巨噬细胞的外泌体中高表达，并且可以被HCC细胞内化。源自M2巨噬细胞外泌体的ETV4在体外促进HCC细胞增殖、糖酵解和干性，并增强裸鼠体内的HCC生长。机制上，ETV4与SULT2B1相互作用并促进其转录。SULT2B1沉默抑制HCC细胞增殖、糖酵解和干性。此外，源自M2巨噬细胞的外泌体ETV4通过调节SULT2B1发挥其作用。
源自M2巨噬细胞外泌体的ETV4通过与SULT2B1相互作用促进HCC细胞增殖、糖酵解和干性，这为开发基于外泌体的HCC治疗方法提供了新的见解。
