title: JAG2 induction in hypoxic tumor cells alters Notch signaling and enhances endothelial cell tube formation.
abstract: Several studies have revealed links between hypoxia and activation of Notch in solid tumors. While most reports have focused on intracellular domain of the Notch1 receptor (icN1) stabilization by direct interaction with HIF proteins, little attention has been given to Notch ligand regulation during hypoxia. Here we show that the Notch ligand JAG2 is transcriptionally activated by hypoxia in a HIF-1α dependent manner. Hypoxic JAG2 induction resulted in elevated Notch activity in tumor cells, as was measured by increased icN1 levels and induction of the Notch target gene HEY1. In primary tumor material, JAG2 expression correlated with vascular development and angiogenesis gene signatures. In line with this, coculture experiments of endothelial cells with hypoxic breast cancer cells displayed a reduction in number of capillary-like tubes formed upon JAG2 siRNA treatment of the breast cancer cells. Together these results suggest that a hypoxic induction of JAG2 in tumor cells mediates a hypoxia-regulated cross-talk between tumor and endothelial cells.
authors.affiliation: Center for Molecular Pathology, Department of Laboratory Medicine, Skåne University Hospital, Entrance 78, SE-205 02 Malmö, Sweden.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pietras
authors.forename: Kristoffer
authors.initials: K
authors.lastname: von Stedingk
authors.forename: David
authors.initials: D
authors.lastname: Lindgren
authors.forename: Sven
authors.initials: S
authors.lastname: Påhlman
authors.forename: Håkan
authors.initials: H
authors.lastname: Axelson
mesh_terms: D042501:Angiogenic Proteins; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072101:Jagged-2 Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D020239:Receptor Cross-Talk; D051881:Receptor, Notch1 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D042501:Angiogenic Proteins; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C485631:HEY1 protein, human; C497442:HIF1A protein, human; C490504:JAG2 protein, human