Id2 promotes tumor cell migration and invasion through transcriptional repression of semaphorin 3F.
Id2 promotes tumor cell migration and invasion through transcriptional repression of semaphorin 3F.
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DOI：
10.1158/0008-5472.can-09-3048
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发表时间：
2010-05-01
期刊：
影响因子：
11.2
通讯作者：
Klagsbrun M
中科院分区：
文献类型：
--
作者：
Coma S;Amin DN;Shimizu A;Lasorella A;Iavarone A;Klagsbrun M
ID蛋白(Id1-4)是促进肿瘤转移的螺旋-环-螺旋转录因子。研究发现，一种有效的肿瘤转移抑制因子信号素3F(Semaphorin 3F，SEMA3F)被Id2抑制。与低转移的肿瘤细胞系相比，高转移的人类肿瘤细胞株具有相对较高的ID2含量和较低的SEMA3F水平。未观察到转移潜能与ID家族其他成员的表达之间的相关性。此外，Id2在低转移肿瘤细胞中的异位表达下调了SEMA3F，因此增强了它们的迁移和侵袭能力，这是体内转移的两个必要步骤。ID2的过度表达是由c-myc癌蛋白驱动的。SEMA3F是E47/Id2途径的直接靶基因。在SEMA3F基因的启动子区域发现了两个E-box位点，它们与包括E47在内的E蛋白转录因子结合。E47直接激活了SEMA3F启动子的活性和表达，并促进了SEMA3F的生物学活性，包括F-肌动蛋白解聚、RhoA失活和抑制细胞迁移。SEMA3F的沉默抑制了E47诱导的SEMA3F的表达和生物学活性，证实了这些作用是SEMA3F依赖的。E47不能诱导SEMA3家族其他成员的表达。显性负性E蛋白抑制剂ID2可阻断E47诱导的SEMA3F表达和生物学活性。因此，高转移的肿瘤细胞过度表达c-myc，导致Id2表达上调；Id2的异常升高抑制了SEMA3F的表达，从而增强了肿瘤细胞的迁移和侵袭能力。
Id proteins (Id1-4) are helix-loop-helix transcription factors that promote metastasis. It was found that Semaphorin 3F (SEMA3F), a potent inhibitor of metastasis, was repressed by Id2. High metastatic human tumor cell lines had relatively high amounts of Id2 and low SEMA3F levels compared to their low metastatic counterparts. No correlation between metastatic potential and expression of the other Id family members was observed. Furthermore, ectopic expression of Id2 in low metastatic tumor cells downregulated SEMA3F and, as a consequence, enhanced their ability to migrate and invade, two requisite steps of metastasis in vivo. Id2 overexpression was driven by the c-myc oncoprotein. SEMA3F was a direct target gene of the E47/Id2 pathway. Two E-box sites, which bind E protein transcription factors including E47, were identified in the promoter region of the SEMA3F gene. E47 directly activated SEMA3F promoter activity and expression and promoted SEMA3F biological activities, including F-actin depolymerization, inactivation of RhoA and inhibition of cell migration. Silencing of SEMA3F inhibited the E47-induced SEMA3F expression and biological activities, confirming that these E47-induced effects were SEMA3F-dependent. E47 did not induce expression of the other members of the SEMA3 family. Id2, a dominant-negative inhibitor of E proteins, abrogated the E47-induced SEMA3F expression and biological activities. Thus, high metastatic tumor cells overexpress c-myc, leading to upregulation of Id2 expression; the aberrantly elevated amount of Id2 represses SEMA3F expression and, as a consequence, enhances the ability of tumor cells to migrate and invade.