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Vol. 16, Issue 4, 1901-1912, April 2005

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Hypoxia-inducible Factor Regulates v3 Integrin Cell Surface Expression

Karen D. Cowden Dahl ^*, Sarah E. Robertson , Valerie M. Weaver  , and M. Celeste Simon ^* ||

^* Abramson Family Cancer Research Institute, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Department of Cell and Developmental Biology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Department of Bioengineering, Institute for Medicine and Engineering, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and ^|| Department of Howard Hughes Medical Institute, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104

Submitted December 15, 2004; Revised January 24, 2005; Accepted January 25, 2005
Monitoring Editor: Marianne Bronner-Fraser

Hypoxia-inducible factor (HIF)-deficient placentas exhibit a number of defects, including changes in cell fate adoption, lack of fetal angiogenesis, hypocellularity, and poor invasion into maternal tissue. HIF is a heterodimeric transcription factor consisting of and aryl hydrocarbon receptor nuclear translocator or ARNT) subunits. We used undifferentiated trophoblast stem (TS) cells to characterize HIF-dependent adhesion, migration, and invasion. Arnt^-/- and Hif^-/- TS cells exhibit reduced adhesion and migration toward vitronectin compared with wild-type cells. Furthermore, this defect is associated with decreased cell surface expression of integrin v3 and significantly decreased expression of this integrin in focal adhesions. Because of the importance of adhesion and migration in tumor progression (in addition to placental development), we examined the affect of culturing B16F0 melanoma cells in 1.5% oxygen (O₂). Culturing B16F0 melanoma cells at 1.5% O₂ resulted in increased v3 integrin surface expression and increased adhesion to and migration toward vitronectin. Together, these data suggest that HIF and O₂ tension influence placental invasion and tumor migration by increasing cell surface expression of v3 integrin.

Address correspondence to: M. Celeste Simon (celeste2{at}mail.med.upenn.edu).

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