EMMPRIN promotes melanoma cells malignant properties through a HIF-2alpha mediated up-regulation of VEGF-receptor-2.
EMMPRIN promotes melanoma cells malignant properties through a HIF-2alpha mediated up-regulation of VEGF-receptor-2.
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DOI：
10.1371/journal.pone.0012265
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发表时间：
2010-08-31
期刊：
影响因子：
3.7
通讯作者：
Mourah S
中科院分区：
文献类型：
--
作者：
Bougatef F;Menashi S;Khayati F;Naïmi B;Porcher R;Podgorniak MP;Millot G;Janin A;Calvo F;Lebbé C;Mourah S
EMMPRIN在黑色素瘤组织中的表达被报道为预后不良的预测因子。在这里，我们证明，EMMPRIN上调VEGF受体-2（VEGFR-2）在两个不同的原发性黑色素瘤细胞系，从而增加这些细胞的迁移和增殖，同时抑制其凋亡。siRNA抑制VEGFR-2表达可消除这些EMMPRIN效应。EMMPRIN对VEGFR-2的调节是通过HIF-2α的过度表达及其易位至细胞核与HIF-1β形成异源二聚体介导的。这些结果得到了EMMPRIN与VEGFR-2在人黑素瘤组织中的表达以及HIF-2α在细胞核中定位程度之间的体内相关性的支持。他们证明了EMMPRIN通过HIF-2α/VEGFR-2介导的机制促进肿瘤进展的新机制，在黑色素瘤细胞恶性肿瘤中具有自分泌作用。因此，在癌症中抑制EMMPRIN可以同时靶向VEGFR-2/VEGF系统和基质降解蛋白酶以阻断肿瘤细胞生长和侵袭。
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-2α and its translocation to the nucleus where it forms heterodimers with HIF-1β. 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-2α localization in the nucleus. They demonstrate a novel mechanism by which EMMPRIN promotes tumor progression through HIF-2α/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.
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