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Cell Rep. 2014 Jan 16;6(1):155-67. doi: 10.1016/j.celrep.2013.12.011. Epub 2014 Jan 2.

Hypoxia induces VEGF-C expression in metastatic tumor cells via a HIF-1α-independent translation-mediated mechanism.

Author information

1
Inserm, U1037, 31432 Toulouse, France; Université de Toulouse, UPS, Cancer Research Center of Toulouse, Equipe Labellisee Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, 31432 Toulouse, France.
2
Vesalius Research Center, VIB, University of Leuven, 3000 Leuven, Belgium.
3
UPR 9002 CNRS-ARN, Université De Strasbourg, IBMC, 67084 Strasbourg, France.
4
Université de Toulouse, UPS, TRADGENE, EA4554, 31432 Toulouse, France.
5
Inserm, U1037, 31432 Toulouse, France; Université de Toulouse, UPS, Cancer Research Center of Toulouse, Equipe Labellisee Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, 31432 Toulouse, France. Electronic address: barbara.garmy-susini@inserm.fr.

Abstract

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 1α (HIF-1α) 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.

PMID:
24388748
DOI:
10.1016/j.celrep.2013.12.011
[Indexed for MEDLINE]
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