Hypoxia Induces VEGF-C Expression in Metastatic Tumor Cells via a HIF-1α-Independent Translation-Mediated Mechanism

• Published in: Cell reports (Cambridge) Vol. 6; no. 1; pp. 155 - 167
• Main Authors: Morfoisse, Florent, Kuchnio, Anna, Frainay, Clement, Gomez-Brouchet, Anne, Delisle, Marie-Bernadette, Marzi, Stefano, Helfer, Anne-Catherine, Hantelys, Fransky, Pujol, Francoise, Guillermet-Guibert, Julie, Bousquet, Corinne, Dewerchin, Mieke, Pyronnet, Stephane, Prats, Anne-Catherine, Carmeliet, Peter, Garmy-Susini, Barbara
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2014; Elsevier
• Subjects: 3' Untranslated Regions; Adaptor Proteins, Signal Transducing - metabolism; Animals; Breast Neoplasms - diagnosis; Breast Neoplasms - metabolism; Carcinoma - diagnosis; Carcinoma - metabolism; Cell Hypoxia; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Human health and pathology; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Life Sciences; Lymphatic Metastasis; Mice; Mice, Inbred C57BL; Mice, Nude; Phosphoproteins - metabolism; Protein Biosynthesis; Toxicology; Transcription, Genetic; Vascular Endothelial Growth Factor C - genetics; Vascular Endothelial Growth Factor C - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.12.011

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.
[Display omitted]
•Hypoxia increases VEGF-C protein levels•The VEGF-C 5′ UTR contains an IRES•Hypoxia in lymph vessels upregulates VEGF-C IRES activity in vivo•Hypoxic induction of VEGF-C protein levels is independent of HIF-1α
Vascular endothelial growth factor C (VEGF-C) synthesis correlates with tumor metastasis to the lymph nodes. In this study, Garmy-Susini and colleagues show that VEGF-C upregulation is induced by hypoxia through a HIF-1α-independent mechanism. The VEGF-C mRNA 5′ untranslated region contains an internal ribosome entry site (IRES) allowing ribosome recruitment during stress to promote translation when cap-dependent translation is decreased. These findings suggest that tumor cells have adopted mechanisms to ensure spreading via lymphatics in oxygen-deprived conditions when metastasizing through hypoxic lymph vessels and lymph nodes.