Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan.
Department of Molecular Oncology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan.
Sci Rep. 2020 Jun 26;10(1):10418. doi: 10.1038/s41598-020-67425-4.
Transcription factor ERG (erythroblast transformation-specific (ETS)-related gene) is essential in endothelial differentiation and angiogenesis, in which microRNA (miR)-200b-3p targeting site is expected by miRNA target prediction database. miR-200b is known decreased in hepatocellular carcinoma (HCC), however, the functional relation between ERG and miR-200b-3p, originating from pre-miR-200b, in HCC angiogenesis remains unclear. We investigated whether hepatocyte-derived miR-200b-3p governs angiogenesis in HCC by targeting endothelial ERG. Levels of miR-200b-3p in HCC tissues were significantly lower than those in adjacent non-HCC tissues. Poorly differentiated HCC cell line expressed lower level of miR-200b-3p compared to well-differentiated HCC cell lines. The numbers of ERG-positive endothelial cells were higher in HCC tissues than in adjacent non-HCC tissues. There was a negative correlation between the number of ERG-positive cells and miR-200b-3p expression in HCC tissues. Culture supernatants of HCC cell lines with miR-200b-3p-overexpression reduced cell migration, proliferation and tube forming capacity in endothelial cells relative to the control, while those with miR-200b-3p-inhibition augmented the responses. Exosomes isolated from HCC culture supernatants with miR-200b-3p overexpression suppressed endothelial ERG expression. These results suggest that exosomal miR-200b-3p from hepatocytes suppresses endothelial ERG expression, and decreased miR-200b-3p in cancer cells promotes angiogenesis in HCC tissues by enhancing endothelial ERG expression.
转录因子 ERG（红细胞生成素转化特异性（ETS）相关基因）在血管内皮分化和血管生成中是必不可少的，miRNA 靶标预测数据库预测 miR-200b-3p 的靶点就在其中。miR-200b 在肝细胞癌（HCC）中表达下调，但 HCC 血管生成中 ERG 与 miR-200b-3p（源于 pre-miR-200b）之间的功能关系尚不清楚。我们通过检测内皮细胞 ERG 靶向肝细胞来源的 miR-200b-3p 是否调节 HCC 血管生成来探讨这个问题。HCC 组织中的 miR-200b-3p 水平明显低于相邻的非 HCC 组织。与分化良好的 HCC 细胞系相比，低分化 HCC 细胞系表达的 miR-200b-3p 水平较低。与相邻的非 HCC 组织相比，HCC 组织中的 ERG 阳性内皮细胞数量较多。HCC 组织中 ERG 阳性细胞数量与 miR-200b-3p 表达呈负相关。与对照组相比，过表达 miR-200b-3p 的 HCC 细胞系的培养上清液可降低内皮细胞的迁移、增殖和管形成能力，而抑制 miR-200b-3p 表达则增强了这些反应。过表达 miR-200b-3p 的 HCC 细胞培养上清液中分离的外泌体可抑制内皮 ERG 表达。这些结果表明，来自肝细胞的外泌体 miR-200b-3p 抑制内皮 ERG 表达，癌细胞中 miR-200b-3p 的下调通过增强内皮 ERG 表达促进 HCC 组织中的血管生成。
