Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is one of the main causes of cancer-related d eath[1]
The expression levels of miR-200b-3p in Human umbilical vein endothelial cells (HUVECs) was extremely low when compared to those in three hepatocellular carcinoma (HCC) cell lines (Fig. 1c). These data indicate that non-cancer tissues, likely non-cancer hepatocytes, exhibit high levels of miR-200b-3p expression, whereas HCC tissues, likely cancer cells, exhibit decreased expression depending on the degree of cancer differentiation
We investigated the role of miR-200b-3p in regulating cancer angiogenesis in HCC
Summary
Hepatocellular carcinoma (HCC) is one of the main causes of cancer-related d eath[1]. MiRNAs regulate angiogenesis by targeting angiogenic factors and protein k inases[6]. Despite aberrant miRNAs expressions in H CC7, it is worthy to note that miR-200b is down-regulated in HCC tissues as compared to adjacent non-cancer tissues[8]. MiR-200b inhibits angiogenesis through direct and indirect mechanisms by targeting interleukin-8 and CXCL1 by tumor endothelial and cancer c ells. ERG plays an essential role in endothelial homeostasis, differentiation, and a ngiogenesis[14,15], in which miR-200b-3p targeting site is expected by miRNA target prediction database. We hypothesized that down-regulated miR-200b-3p in HCC may cause enhanced endothelial ERG expression, leading to increased angiogenesis in the cancer microenvironment. We demonstrate that HCC tissues exhibit reduced miR-200b-3p expression, which causes augmented endothelial ERG expression, promoting angiogenesis in the cancer microenvironment. MiR-200b-3p can be a novel therapeutic target for the regulation of cancer angiogenesis
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