Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1

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

Research output: Contribution to journalArticlepeer-review

Abstract

Hypoxia-inducible factor 1 (HIF-1) transactivates genes the products of which mediate tumor angiogenesis and glycolytic metabolism. Overexpression of the HIF-1α 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-1α overexpression stimulates Matrigel invasion by HCT116 human colon carcinoma cells, whereas this process is inhibited by a small interfering RNA directed against HIF-1α. 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 α; 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-1α overexpression. These results provide a molecular basis for promotion of the invasive cancer phenotype by hypoxia and/or HIF-1α overexpression.

Original languageEnglish (US)
Pages (from-to)1138-1143
Number of pages6
JournalCancer Research
Volume63
Issue number5
StatePublished - Mar 1 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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