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Blood. 2008 Feb 1;111(3):1217-26. Epub 2007 Oct 23.

Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes GAX and HOXA5.

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  • 1Division of Surgical Oncology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, The Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA.

Abstract

Angiogenesis is critical to tumor progression. The homeobox gene GAX inhibits angiogenesis in vascular endothelial cells (ECs). We have identified a microRNA (miR-130a) that regulates GAX expression and hypothesized that it plays a major role in modulating GAX activity in ECs. A 280-bp fragment from the GAX 3'-untranslated region (3'-UTR) containing 2 miR-130a targeting sites was observed to be required for the rapid down-regulation of GAX expression by serum and proangiogenic factors, whereas the activity of the GAX promoter did not vary with exposure to serum or proangiogenic factors. This same 280-bp sequence in the GAX 3'-UTR cloned into the psiCHECK2-Luciferase vector mediated serum-induced down-regulation of the reporter gene when placed 3' of it. Finally, forced expression of miR-130a inhibits GAX expression through this specific GAX 3'-UTR sequence. A genome-wide search for other possible miR-130a binding sites revealed an miR-130a targeting site in the 3'-UTR of the antiangiogenic homeobox gene HOXA5, the expression and antiangiogenic activity of which are also inhibited by miR-130a. From these data, we conclude that miR-130a is a regulator of the angiogenic phenotype of vascular ECs largely through its ability to modulate the expression of GAX and HOXA5.

PMID:
17957028
[PubMed - indexed for MEDLINE]
PMCID:
PMC2214763
Free PMC Article
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