Regulation of Colon Carcinoma Cell Invasion by Hypoxia-Inducible Factor 1

Tumor Biology

Regulation of Colon Carcinoma Cell Invasion by Hypoxia-Inducible Factor 1¹

Balaji Krishnamachary, Shannon Berg-Dixon, Brian Kelly, Faton Agani, David Feldser, Gloria Ferreira, Narayan Iyer, Jessica LaRusch, Brian Pak, Panthea Taghavi and Gregg L. Semenza²

McKusick-Nathans Institute of Genetic Medicine and Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3914

Hypoxia-inducible factor 1 (HIF-1) transactivates genes theproducts of which mediate tumor angiogenesis and glycolyticmetabolism. Overexpression of the HIF-1 ${alpha}$ subunit, resulting fromintratumoral hypoxia and genetic alterations, has been demonstratedin common human cancers and is correlated with tumor angiogenesisand patient mortality. Here we demonstrate that hypoxia or HIF-1 ${alpha}$ overexpression stimulates Matrigel invasion by HCT116 humancolon carcinoma cells, whereas this process is inhibited bya small interfering RNA directed against HIF-1 ${alpha}$ . We show thatHIF-1 regulates the expression of genes encoding cathepsin D;matrix metalloproteinase 2; urokinase plasminogen activatorreceptor (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 pathophysiologyof invasion. Neutralizing antibodies against uPAR block tumorcell invasion induced by hypoxia or HIF-1 ${alpha}$ overexpression. Theseresults provide a molecular basis for promotion of the invasivecancer phenotype by hypoxia and/or HIF-1 ${alpha}$ overexpression.

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