Morfoisse F, Tatin F, Hantelys F, Adoue A, Helfer AC, Cassant-Sourdy S, Pujol F, Gomez-Brouchet A, Ligat L, Lopez F, Pyronnet S, Courty J, Guillermet-Guibert J, Marzi S, Schneider RJ, Prats AC, Garmy-Susini BH -01/08/2016
Cancer Res. 2016 Aug 1;76(15):4394-405. doi: 10.1158/0008-5472.CAN-15-3140.
The vascular endothelial growth factor VEGF-D promotes metastasis by inducing lymphangiogenesis and dilatation of the lymphatic vasculature, facilitating tumor cell extravasion. Here we report a novel level of control for VEGF-D expression at the level of protein translation. In human tumor cells, VEGF-D colocalized with eIF4GI and 4E-BP1, which can program increased initiation at IRES motifs on mRNA by the translational initiation complex. In murine tumors, the steady-state level of VEGF-D protein was increased despite the overexpression and dephosphorylation of 4E-BP1, which downregulates protein synthesis, suggesting the presence of an internal ribosome entry site (IRES) in the 5′ UTR of VEGF-D mRNA. We found that nucleolin, a nucleolar protein involved in ribosomal maturation, bound directly to the 5’UTR of VEGF-D mRNA, thereby improving its translation following heat shock stress via IRES activation. Nucleolin blockade by RNAi-mediated silencing or pharmacologic inhibition reduced VEGF-D translation along with a subsequent constriction of lymphatic vessels in tumors. Our results identify nucleolin as a key regulator of VEGF-D expression, deepening understanding of lymphangiogenesis control during tumor formation. Cancer Res; 76(15); 4394-405. ©2016 AACR.
©2016 American Association for Cancer Research.