title: EMMPRIN promotes melanoma cells malignant properties through a HIF-2alpha mediated up-regulation of VEGF-receptor-2.
abstract: 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.
authors.affiliation: Inserm, UMR-S 940 Laboratoire de Pharmacologie, Paris, France.
authors.forename: Faten
authors.initials: F
authors.lastname: Bougatef
authors.forename: Suzanne
authors.initials: S
authors.lastname: Menashi
authors.forename: Farah
authors.initials: F
authors.lastname: Khayati
authors.forename: Benyoussef
authors.initials: B
authors.lastname: Naïmi
authors.forename: Raphaël
authors.initials: R
authors.lastname: Porcher
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Podgorniak
authors.forename: Guy
authors.initials: G
authors.lastname: Millot
authors.forename: Anne
authors.initials: A
authors.lastname: Janin
authors.forename: Fabien
authors.initials: F
authors.lastname: Calvo
authors.forename: Céleste
authors.initials: C
authors.lastname: Lebbé
authors.forename: Samia
authors.initials: S
authors.lastname: Mourah
mesh_terms: 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
chemical_list: 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
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