Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes GAX and HOXA5.
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.
Chen
Yun
Y
Division 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.
Gorski
David H
DH
D020413:3' Untranslated Regions / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics*; D042783:Endothelial Cells / Q000378:metabolism; D015870:Gene Expression; D017930:Genes, Reporter / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D044967:Serum; D014470:Umbilical Cord / Q000378:metabolism
D020413:3' Untranslated Regions; D020533:Angiogenesis Inhibitors; C489213:HOXA5 protein, human; D018398:Homeodomain Proteins; C484193:MEOX2 protein, human; D035683:MicroRNAs