Sprouty1, a new target of the angiostatic agent 16K prolactin, negatively regulates angiogenesis.
BACKGROUND
Disorganized angiogenesis is associated with several pathologies, including cancer. The identification of new genes that control tumor neovascularization can provide novel insights for future anti-cancer therapies. Sprouty1 (SPRY1), an inhibitor of the MAPK pathway, might be one of these new genes. We identified SPRY1 by comparing the transcriptomes of untreated endothelial cells with those of endothelial cells treated by the angiostatic agent 16 K prolactin (16 K hPRL). In the present study, we aimed to explore the potential function of SPRY1 in angiogenesis.


RESULTS
We confirmed 16 K hPRL induced up-regulation of SPRY1 in primary endothelial cells. In addition, we demonstrated the positive SPRY1 regulation in a chimeric mouse model of human colon carcinoma in which 16 K hPRL treatment was shown to delay tumor growth. Expression profiling by qRT-PCR with species-specific primers revealed that induction of SPRY1 expression by 16 K hPRL occurs only in the (murine) endothelial compartment and not in the (human) tumor compartment. The regulation of SPRY1 expression was NF-κB dependent. Partial SPRY1 knockdown by RNA interference protected endothelial cells from apoptosis as well as increased endothelial cell proliferation, migration, capillary network formation, and adhesion to extracellular matrix proteins. SPRY1 knockdown was also shown to affect the expression of cyclinD1 and p21 both involved in cell-cycle regulation. These findings are discussed in relation to the role of SPRY1 as an inhibitor of ERK/MAPK signaling and to a possible explanation of its effect on cell proliferation.


CONCLUSIONS
Taken together, these results suggest that SPRY1 is an endogenous angiogenesis inhibitor.
Sabatel
Céline
C
Unit of Molecular Biology and Genetic Engineering, GIGA-research, University of Liège, B34, Avenue de l'Hôpital, 1, Liège, Belgium.
Cornet
Anne M
AM
Tabruyn
Sébastien P
SP
Malvaux
Ludovic
L
Castermans
Karolien
K
Martial
Joseph A
JA
Struman
Ingrid
I
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011388:Prolactin / Q000378:metabolism* / Q000494:pharmacology; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D010446:Peptide Fragments; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C486055:SPRY1 protein, human; C425468:Spry1 protein, mouse; C503760:prolactin 16-kDa fragment, human; D011388:Prolactin
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