AI Article Synopsis
- Tumors spread to distant organs through lymph vessels and lymph nodes, but the role of hypoxia in promoting lymphangiogenesis is not well understood.
- Hypoxia lowers the transcription and translation of VEGF-C due to increased levels of 4E-BP1, but it can still kickstart VEGF-C translation through an IRES mechanism.
- The IRES activity for VEGF-C is notably higher in tumor cells within lymph nodes than in primary tumors, suggesting that the severe hypoxic conditions in lymph nodes may enhance lymphatic metastasis.
Article 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.
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| http://dx.doi.org/10.1016/j.celrep.2013.12.011 | DOI Listing |
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