Endocan is a VEGF-A and PI3K regulated gene with increased expression in human renal cancer.
An in vitro model of VEGF-A-induced angiogenesis was used to generate transcription profiles of human microvascular endothelial cells. Microarray analysis showed increased transcription of genes known to regulate angiogenesis, but also genes that previously have not been firmly associated with angiogenesis such as endocan, pinin, plakophilin, phosphodiesterase 4B and gelsolin. Increased endocan mRNA levels in response to VEGF-A in endothelial cells and in human renal cancer have previously been reported. We now show increased endocan protein levels in VEGF-A treated endothelial cells and in human renal clear cell carcinoma. Increased protein expression was observed both in tumor cells and in a subset of tumor vessels, while expression in normal kidney tissue was low. VEGF-A seemed to be a specific inducer of endocan transcription since FGF-2, PDGF-BB, HGF/SF and EGF did not alter expression levels. Inhibition of PI3K with LY294002 caused a 12-fold increase in endocan transcription suggesting a repressive function of PI3K. In contrast inhibition of Src or MEK, which are signaling pathways activated by VEGF-A, did not influence basal or VEGF-A-induced endocan levels. In conclusion our study shows that, among angiogenic growth factors, VEGF-A is a specific inducer of endocan transcription which is translated into increased protein levels in VEGF-A treated endothelial cells. Increased endocan protein expression in human renal cancer suggests a role in tumor growth.
Rennel
Emma
E
Department of Genetics and Pathology, the Rudbeck Laboratory, Uppsala University, S-751 85 Uppsala, Sweden.
Mellberg
Sofie
S
Dimberg
Anna
A
Petersson
Ludvig
L
Botling
Johan
J
Ameur
Adam
A
Westholm
Jakub Orzechowski
JO
Komorowski
Jan
J
Lassalle
Philippe
P
Cross
Michael J
MJ
Gerwins
Pär
P
D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism* / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011509:Proteoglycans / Q000378:metabolism* / Q000494:pharmacology; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C101134:ESM1 protein, human; C467484:VEGFA protein, human