EMMPRIN promotes melanoma cells malignant properties through a HIF-2alpha mediated up-regulation of VEGF-receptor-2.
EMMPRIN's expression in melanoma tissue was reported to be predictive of poor prognosis. Here we demonstrate that EMMPRIN up-regulated VEGF receptor-2 (VEGFR-2) in two different primary melanoma cell lines and consequently increased migration and proliferation of these cells while inhibiting their apoptosis. SiRNA inhibition of VEGFR-2 expression abrogated these EMMPRIN effects. EMMPRIN regulation of VEGFR-2 was mediated through the over-expression of HIF-2alpha and its translocation to the nucleus where it forms heterodimers with HIF-1beta. These results were supported by an in vivo correlation between the expression of EMMPRIN with that of VEGFR-2 in human melanoma tissues as well as with the extent of HIF-2alpha localization in the nucleus. They demonstrate a novel mechanism by which EMMPRIN promotes tumor progression through HIF-2alpha/VEGFR-2 mediated mechanism, with an autocrine role in melanoma cell malignancy. The inhibition of EMMPRIN in cancer may thus simultaneously target both the VEGFR-2/VEGF system and the matrix degrading proteases to block tumor cell growth and invasion.
Bougatef
Faten
F
Inserm, UMR-S 940 Laboratoire de Pharmacologie, Paris, France.
Menashi
Suzanne
S
Khayati
Farah
F
Naïmi
Benyoussef
B
Porcher
Raphaël
R
Podgorniak
Marie-Pierre
MP
Millot
Guy
G
Janin
Anne
A
Calvo
Fabien
F
Lebbé
Céleste
C
Mourah
Samia
S
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019898:Autocrine Communication / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D051926:Basigin / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D006224:Cricetinae; D003412:Cricetulus; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000235:genetics; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051926:Basigin; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099162:Endothelial PAS Domain-Containing Protein 1
Mol Cell Biol. 2003 Jul;23(14):4959-71
12832481
Cancer Res. 2005 Apr 15;65(8):3193-9
15833850
Biochem Biophys Res Commun. 2008 Sep 12;374(1):111-6
18616931
Clin Cancer Res. 2009 Feb 1;15(3):1076-85
19188183
Am J Pathol. 2001 Jul;159(1):223-35
11438469
Oncogene. 2007 May 10;26(21):2997-3005
17130836
Cancer Res. 2007 Jan 1;67(1):9-15
17210677
Nat Med. 2003 Jun;9(6):669-76
12778165
Biochem Biophys Res Commun. 1995 Dec 26;217(3):721-7
8554590
Curr Top Dev Biol. 2003;54:371-89
12696756
Melanoma Res. 1997 Aug;7 Suppl 2:S19-26
9578413
Am J Pathol. 1997 Sep;151(3):665-70
9284814
Pathol Int. 2006 Jul;56(7):359-67
16792544
Histol Histopathol. 2003 Jul;18(3):981-7
12792908
Am J Pathol. 2005 Jan;166(1):209-19
15632013
J Invest Dermatol. 2004 Jul;123(1):72-7
15191545
Cancer Res. 2006 Dec 1;66(23):11323-30
17145878
Nat Rev Cancer. 2004 Nov;4(11):891-9
15516961
Cancer Invest. 2009 Mar;27(3):329-33
19160100
J Clin Oncol. 2009 Jun 10;27(17):2823-30
19349552
Cancer Res. 2008 Mar 1;68(5):1581-92
18316624
Cancer Lett. 2009 Jan 8;273(1):140-7
18778892
Thromb Haemost. 2005 Feb;93(2):199-204
15711733
J Invest Dermatol. 2004 Dec;123(6):1151-61
15610528
Int J Oncol. 2005 Dec;27(6):1625-32
16273219
PLoS Med. 2007 Jun;4(6):e186
17550303
Int J Cancer. 2002 Jun 1;99(4):520-8
11992541
Connect Tissue Res. 2008;49(3):175-9
18661337
Cancer Res. 1995 Jan 15;55(2):434-9
7812975
Melanoma Res. 2005 Feb;15(1):39-43
15714119
J Biol Chem. 2003 Feb 28;278(9):7520-30
12464608
Cell Cycle. 2007 Apr 15;6(8):919-26
17404509
Cancer Res. 2007 May 1;67(9):4182-9
17483329