MicroRNA-519c suppresses hypoxia-inducible factor-1α expression and tumor angiogenesis
Journal
Cancer Research
Journal Volume
70
Journal Issue
7
Pages
2675-2685
Date Issued
2010
Author(s)
Cha S.-T.
Chen P.-S.
Johansson G.
Wang M.-Y.
Jee S.-H.
Kuo M.-L.
Abstract
Hypoxia-inducible factor-1α (HIF-1α) is widely considered to be one of the key regulators of tumor angiogenesis. The upstream regulation is complex and involves several growth factors, cytokines, and hypoxia Herein, we have identified miR-519c as a hypoxia-independent regulator of HIF-1α, acting through direct binding to the HIF-1α 3' untranslated region and leading to reduced tumor angiogenesis. Overexpression of miR-519c resulted in a significant decrease of HIF-1α protein levels and reduced the tube formation of human umbilical vein endothelial cells; similarly, antagomir inhibition of miR-519c increased the level of HIF-1α protein and enhanced angiogenic activity, suggesting an important role of miR-519c in HIF-1α-mediated angiogenesis. Consistent with the overexpression of miR-519c in cancer patients with better prognosis, mice injected with miR-519c-overexpressing cells exhibited dramatically reduced HIF-1α levels, followed by suppressed tumor angiogenesis, growth, and metastasis. In addition, we found that hepatocyte growth factor (HGF), a known HIF-1α inducer, reduced the miR-519c levels through an Akt-dependent pathway. This regulation was posttranscriptional and may be mediated by suppression of miR-519c maturation. Taken together, our findings provide the first evidence that miR-519c is a pivotal regulator of tumor angiogenesis and that microenvironmental HGF contributes to regulating miR-519c biogenesis in cancer cells. ?2010 American Association for Cancer Research.
SDGs
Other Subjects
hypoxia inducible factor 1alpha; micro rna 519c; microRNA; scatter factor; unclassified drug; 3' untranslated region; angiogenesis; animal experiment; animal model; animal tissue; article; controlled study; endothelium cell; male; metastasis; mouse; nonhuman; priority journal; prognosis; tumor angiogenesis; umbilical vein
Publisher
American Association for Cancer Research Inc.
Type
journal article