Nucleolin Promotes Heat Shock-Associated Translation of VEGF-D to Promote Tumor Lymphangiogenesis.
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.
UMR 1048-1I2MC, Université de Toulouse, Inserm, UPS, Toulouse, France.
Florent
F
Morfoisse
UMR 1048-1I2MC, Université de Toulouse, Inserm, UPS, Toulouse, France.
Florence
F
Tatin
UMR 1048-1I2MC, Université de Toulouse, Inserm, UPS, Toulouse, France.
Fransky
F
Hantelys
UMR 1048-1I2MC, Université de Toulouse, Inserm, UPS, Toulouse, France.
Aurelien
A
Adoue
IBMC-CNRS, Université de Strasbourg, Strasbourg, France.
Anne-Catherine
AC
Helfer
UMR 1037-CRCT, Inserm, UPS, Toulouse, France.
Stephanie
S
Cassant-Sourdy
UMR 1048-1I2MC, Université de Toulouse, Inserm, UPS, Toulouse, France.
Françoise
F
Pujol
UMR 5089-IPBS, CNRS, UPS, Toulouse, France. Department of Pathology, IUCT-Oncopole, Toulouse, France.
Anne
A
Gomez-Brouchet
Pôle Technologique du CRCT - INSERM-UMR1037, Toulouse, France.
Laetitia
L
Ligat
Pôle Technologique du CRCT - INSERM-UMR1037, Toulouse, France.
Frederic
F
Lopez
UMR 1037-CRCT, Inserm, UPS, Toulouse, France.
Stephane
S
Pyronnet
Laboratoire CRRET Laboratory, Université Paris EST Créteil, Créteil, France.
Jose
J
Courty
UMR 1037-CRCT, Inserm, UPS, Toulouse, France.
Julie
J
Guillermet-Guibert
IBMC-CNRS, Université de Strasbourg, Strasbourg, France.
Stefano
S
Marzi
NYU School of Medicine, New York, New York.
Robert J
RJ
Schneider
UMR 1048-1I2MC, Université de Toulouse, Inserm, UPS, Toulouse, France.
Anne-Catherine
AC
Prats
UMR 1048-1I2MC, Université de Toulouse, Inserm, UPS, Toulouse, France. barbara.garmy-susini@inserm.fr.
Barbara H
BH
Garmy-Susini
D000818:Animals; D006801:Humans; D042583:Lymphangiogenesis / Q000235:genetics*; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D014162:Transfection; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism*; D000097796:Nucleolin
D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D042643:Vascular Endothelial Growth Factor D; D000097796:Nucleolin