VEGFA Expression Is Inhibited by Arsenic Trioxide in HUVECs through the Upregulation of Ets-2 and miRNA-126.
Arsenic trioxide (ATO) has been used to treat patients with acute promyelocytic leukemia. Recently, studies have shown that ATO can induce apoptosis in leukemic cells and blood vessel endothelial cells in a time- and dose-dependent manner through the inhibition of vascular endothelial growth factor A (VEGFA) production. VEGFA is a key factor in angiogenesis initiation. Targeted inhibition of VEGF or VEGFA expression can suppress angiogenesis; however, little is known about the mechanism by which ATO inhibits VEGFA expression. In this study, we investigated the role of miRNA-126 in the mechanism of action of ATO in human umbilical vein endothelial cells (HUVECs). ATO significantly decreased the viability and proliferation of HUVECs and decreased their migration at 48 h. Cell proliferation was inhibited by 50% (IC50) when 5.0 μmol/L ATO was used. ATO treatment induced miR-126 upregulation and HUVEC apoptosis. Transfection with a miR-126 mimic significantly downregulated VEGFA mRNA levels, and transfection with a miR-126 inhibitor significantly upregulated VEGFA mRNA levels. Finally, we showed that ATO treatment upregulated Ets-2 and miR-126 expression in HUVECs. These results demonstrate that ATO inhibits the growth of HUVECs and induces apoptosis by downregulating VEGFA. One mechanism by which this occurs is Ets-2 upregulation, which results in an increase in miR-126 levels and downregulation of VEGFA expression.
Key Laboratory of Harbin Medical University Eye Center, Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin, China.
Hong-Yan
HY
Ge
Daqing Oilfield General Hospital,9 ZhongKang street, Saertu District of Daqing, China; Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
Zhong-Jing
ZJ
Han
Key Laboratory of Harbin Medical University Eye Center, Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin, China.
Pei
P
Tian
Key Laboratory of Harbin Medical University Eye Center, Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin, China; Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Key Laboratory of Myocardial Ischemia Mechanism and Treatment (Harbin Medical University), Ministry of Education, Baojian Road, Harbin, Heilongjiang Province, PR China.
Wen-Jie
WJ
Sun
Key Laboratory of Harbin Medical University Eye Center, Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin, China.
Da-Xi
DX
Xue
Key Laboratory of Harbin Medical University Eye Center, Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin, China.
Yu
Y
Bi
Key Laboratory of Harbin Medical University Eye Center, Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin, China.
Zhang-Hui
ZH
Yang
Key Laboratory of Harbin Medical University Eye Center, Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin, China.
Ping
P
Liu
D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis*; D010087:Oxides / Q000494:pharmacology*; D050787:Proto-Oncogene Protein c-ets-2 / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D001152:Arsenicals; C494069:ETS2 protein, human; C527111:MIRN126 microRNA, human; D035683:MicroRNAs; D010087:Oxides; D050787:Proto-Oncogene Protein c-ets-2; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077237:Arsenic Trioxide