Journal
CELL REPORTS
Volume 6, Issue 1, Pages 155-167Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2013.12.011
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Funding
- Ligue Regionale Contre le Cancer
- Fondation pour la Recherche Medicale
- Association Francaise contre les Myopathies
- Association pour la Recherche sur le Cancer
- Conseil Regional Midi-Pyrenees (France)
- Belgian Science Fund-Flanders
- Long-term Structural Funding Methusalem by the Flemish Government
- Interuniversitary Actraction Poles [P7/03]
- Belgian Government
- Leducq Transatlantic Network-Artemis
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Various tumors metastasize via lymph vessels and lymph nodes to distant organs. Even though tumors are hypoxic, the mechanisms of how hypoxia regulates lymphangiogenesis remain poorly characterized. Here, we show that hypoxia reduced vascular endothelial growth factor C (VEGF-C) transcription and cap-dependent translation via the upregulation of hypophosphorylated 4E-binding protein 1 (4E-BP1). However, initiation of VEGF-C translation was induced by hypoxia through an internal ribosome entry site (IRES)-dependent mechanism. IRES-dependent VEGF-C translation was independent of hypoxia-inducible factor 1 alpha (HIF-1 alpha) signaling. Notably, the VEGF-C IRES activity was higher in metastasizing tumor cells in lymph nodes than in primary tumors, most likely because lymph vessels in these lymph nodes were severely hypoxic. Overall, this transcription-independent but translation-dependent upregulation of VEGF-C in hypoxia stimulates lymphangiogenesis in tumors and lymph nodes and may contribute to lymphatic metastasis.
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