Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1.
Hypoxia-inducible factor 1 (HIF-1) transactivates genes the products of which mediate tumor angiogenesis and glycolytic metabolism. Overexpression of the HIF-1 alpha subunit, resulting from intratumoral hypoxia and genetic alterations, has been demonstrated in common human cancers and is correlated with tumor angiogenesis and patient mortality. Here we demonstrate that hypoxia or HIF-1 alpha overexpression stimulates Matrigel invasion by HCT116 human colon carcinoma cells, whereas this process is inhibited by a small interfering RNA directed against HIF-1 alpha. We show that HIF-1 regulates the expression of genes encoding cathepsin D; matrix metalloproteinase 2; urokinase plasminogen activator receptor (uPAR); fibronectin 1; keratins 14, 18, and 19; vimentin; transforming growth factor alpha; and autocrine motility factor, which are proteins that play established roles in the pathophysiology of invasion. Neutralizing antibodies against uPAR block tumor cell invasion induced by hypoxia or HIF-1 alpha overexpression. These results provide a molecular basis for promotion of the invasive cancer phenotype by hypoxia and/or HIF-1 alpha overexpression.
Krishnamachary
Balaji
B
McKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3914, USA.
Berg-Dixon
Shannon
S
Kelly
Brian
B
Agani
Faton
F
Feldser
David
D
Ferreira
Gloria
G
Iyer
Narayan
N
LaRusch
Jessica
J
Pak
Brian
B
Taghavi
Panthea
P
Semenza
Gregg L
GL
D000818:Animals; D001485:Basement Membrane / Q000166:cytology / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D055293:Receptors, Urokinase Plasminogen Activator; D014157:Transcription Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014157:Transcription Factors