title: Hypoxia induces VEGF-C expression in metastatic tumor cells via a HIF-1α-independent translation-mediated mechanism.
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.
authors.affiliation: 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.
authors.forename: Florent
authors.initials: F
authors.lastname: Morfoisse
authors.affiliation: Vesalius Research Center, VIB, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Anna
authors.initials: A
authors.lastname: Kuchnio
authors.affiliation: 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.
authors.forename: Clement
authors.initials: C
authors.lastname: Frainay
authors.affiliation: 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.
authors.forename: Anne
authors.initials: A
authors.lastname: Gomez-Brouchet
authors.affiliation: 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.
authors.forename: Marie-Bernadette
authors.initials: MB
authors.lastname: Delisle
authors.affiliation: UPR 9002 CNRS-ARN, Université De Strasbourg, IBMC, 67084 Strasbourg, France.
authors.forename: Stefano
authors.initials: S
authors.lastname: Marzi
authors.affiliation: UPR 9002 CNRS-ARN, Université De Strasbourg, IBMC, 67084 Strasbourg, France.
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Helfer
authors.affiliation: Université de Toulouse, UPS, TRADGENE, EA4554, 31432 Toulouse, France.
authors.forename: Fransky
authors.initials: F
authors.lastname: Hantelys
authors.affiliation: Université de Toulouse, UPS, TRADGENE, EA4554, 31432 Toulouse, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Pujol
authors.affiliation: 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.
authors.forename: Julie
authors.initials: J
authors.lastname: Guillermet-Guibert
authors.affiliation: 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.
authors.forename: Corinne
authors.initials: C
authors.lastname: Bousquet
authors.affiliation: Vesalius Research Center, VIB, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.affiliation: 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.
authors.forename: Stephane
authors.initials: S
authors.lastname: Pyronnet
authors.affiliation: Université de Toulouse, UPS, TRADGENE, EA4554, 31432 Toulouse, France.
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Prats
authors.affiliation: Vesalius Research Center, VIB, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.affiliation: 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.
authors.forename: Barbara
authors.initials: B
authors.lastname: Garmy-Susini
mesh_terms: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D002277:Carcinoma / Q000175:diagnosis / Q000378:metabolism*; D018797:Cell Cycle Proteins; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008207:Lymphatic Metastasis; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D010750:Phosphoproteins / Q000378:metabolism; D014176:Protein Biosynthesis; D014158:Transcription, Genetic; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010750:Phosphoproteins; D042582:Vascular Endothelial Growth Factor C