title: Hypoxia-inducible factor regulates alphavbeta3 integrin cell surface expression.
abstract: 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 alpha and beta 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 Hifalpha(-/-) 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 alphavbeta3 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 (O(2)). Culturing B16F0 melanoma cells at 1.5% O(2) resulted in increased alphavbeta3 integrin surface expression and increased adhesion to and migration toward vitronectin. Together, these data suggest that HIF and O(2) tension influence placental invasion and tumor migration by increasing cell surface expression of alphavbeta3 integrin.
authors.affiliation: Abramson Family Cancer Research Institute, School of Medicine, University of Pennsylvania, Philadelphia, 19104, USA.
authors.forename: Karen D
authors.initials: KD
authors.lastname: Cowden Dahl
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Robertson
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Weaver
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D002448:Cell Adhesion; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010100:Oxygen / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039302:Integrin alphaVbeta3; D010100:Oxygen; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C497397:Arnt protein, mouse