Loss of AP-2 results in downregulation of c-KIT and enhancement of melanoma tumorigenicity and metastasis
Loss of AP-2 results in downregulation of c-KIT and enhancement of melanoma tumorigenicity and metastasis
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DOI：
10.1093/emboj/17.15.4358
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发表时间：
1998-08-03
期刊：
影响因子：
11.4
通讯作者：
Bar-Eli, M
中科院分区：
文献类型：
--
作者：
Huang, S;Jean, D;Bar-Eli, M
酪氨酸激酶受体c-KIT的表达在人黑色素瘤的局部肿瘤生长和侵袭过程中逐渐降低。我们先前已经表明，在高转移性细胞中强制c-KIT表达抑制裸鼠肿瘤生长和转移。此外，c-KIT的配体SCF在体外和体内条件下诱导表达c-KIT的人黑素瘤细胞凋亡。在这里，我们表明，在高转移性细胞中c-KIT表达的损失与转录因子AP-2的表达的损失相关。c-KIT启动子含有AP-2的三个结合位点，EMSA凝胶表明AP-2蛋白直接结合到c-KIT启动子。将野生型AP-2转染入c-KIT阴性A375 SM黑色素瘤细胞激活了c-KIT启动子驱动的荧光素酶报告基因，而在c-KIT阳性Mel-501细胞中表达显性阴性AP-2B抑制了其激活。AP-2转染的A375 SM细胞内源性c-KIT mRNA和蛋白表达上调，而对照细胞无此变化。此外，AP-2在A375 SM细胞中的再表达抑制了其在裸鼠体内的致瘤性和转移潜能。这些结果表明，c-KIT的表达受AP-2的高度调节，AP-2的表达抑制了人黑色素瘤细胞的致瘤性和转移潜能，可能通过c-KIT的反式激活和SCF诱导的细胞凋亡。因此，AP-2表达的缺失可能是恶性黑色素瘤发生发展的关键事件。
Expression of the tyrosine kinase receptor, c-KIT, progressively decreases during local tumor growth and invasion of human melanomas, We have previously shown that enforced c-KIT expression in highly metastatic cells inhibited tumor growth and metastasis in nude mice. Furthermore, the ligand for c-KIT, SCF, induces apoptosis in human melanoma cells expressing c-KIT under both in vitro and in vivo conditions. Here we show that loss of c-KIT expression in highly metastatic cells correlates with loss of expression of the transcription factor AP-2, The c-KIT promoter contains three binding sites for AP-2 and EMSA gels demonstrated that AP-2 protein binds directly to the c-KIT promoter. Transfection of wild-type AP-2 into c-KIT-negative A375SM melanoma cells activated a c-KIT promoter-driven luciferase reporter gene, while expression of a dominant-negative AP-2B in c-KIT-positive Mel-501 cells inhibited its activation. Endogenous c-KIT mRNA and expression of proteins were upregulated in AP-2-transfected cells, but not in control cells, In addition, re-expression of AP-2 in A375SM cells suppressed their tumorigenicity and metastatic potential in nude mice. These results indicate that the expression of c-KIT is highly regulated by AP-2 and that enforced AP-2 expression suppresses tumorigenicity and metastatic potential of human melanoma cells, possibly through c-KIT transactivation and SCF-induced apoptosis, Therefore, loss of AP-2 expression might be a crucial event in the development of malignant melanoma.