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Cancer Res. 2016 Aug 1;76(15):4394-405. doi: 10.1158/0008-5472.CAN-15-3140. Epub 2016 Jun 8.

Nucleolin Promotes Heat Shock-Associated Translation of VEGF-D to Promote Tumor Lymphangiogenesis.

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UMR 1048-1I2MC, Université de Toulouse, Inserm, UPS, Toulouse, France.
IBMC-CNRS, Université de Strasbourg, Strasbourg, France.
UMR 1037-CRCT, Inserm, UPS, Toulouse, France.
UMR 5089-IPBS, CNRS, UPS, Toulouse, France. Department of Pathology, IUCT-Oncopole, Toulouse, France.
Pôle Technologique du CRCT - INSERM-UMR1037, Toulouse, France.
Laboratoire CRRET Laboratory, Université Paris EST Créteil, Créteil, France.
NYU School of Medicine, New York, New York.
UMR 1048-1I2MC, Université de Toulouse, Inserm, UPS, Toulouse, France.


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.

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