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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenic Proteins
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Breast Neoplasms / blood supply
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Breast Neoplasms / genetics*
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Breast Neoplasms / pathology
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Hypoxia
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Coculture Techniques
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Endothelial Cells / metabolism*
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Endothelial Cells / pathology
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Endothelium, Vascular / metabolism
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Female
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Jagged-2 Protein
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Neovascularization, Pathologic / genetics
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering
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Receptor Cross-Talk
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Receptor, Notch1 / metabolism*
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Tumor Cells, Cultured
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Angiogenic Proteins
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Basic Helix-Loop-Helix Transcription Factors
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Cell Cycle Proteins
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HEY1 protein, human
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Intercellular Signaling Peptides and Proteins
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JAG2 protein, human
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Jagged-2 Protein
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Membrane Proteins
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RNA, Messenger
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RNA, Small Interfering
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Receptor, Notch1
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Vascular Endothelial Growth Factor A
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endothelial PAS domain-containing protein 1