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

作者：Morfoisse Florent; Tatin Florence; Hantelys Fransky; Adoue Aurelien; Helfer Anne Catherine; Cassant Sourdy Stephanie; Pujol Francoise; Gomez Brouchet Anne; Ligat Laetitia; Lopez Frederic; Pyronnet Stephane; Courty Jose; Guillermet Guibert Julie; Marzi Stefano; Schneider Robert J; Prats Anne Catherine; Garmy Susini Barbara H^*

来源：Cancer Research, 2016, 76(15): 4394-4405.

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.

• 出版日期2016-8-1