NF-κB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4
NF-κB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4
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DOI：
10.1074/jbc.m300609200
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发表时间：
2003-06-13
影响因子：
4.8
通讯作者：
Nakshatri, H
中科院分区：
文献类型：
--
作者：
Helbig, G;Christopherson, KW;Nakshatri, H
癌细胞的转移是一个复杂的过程，涉及多个步骤，包括侵袭，血管生成以及通过血管进行癌细胞的运输，渗出，器官特异性归因和生长。基质金属蛋白酶，尿激酶型纤溶酶原激活剂和细胞因子在侵袭和血管生成中起主要作用，而趋化因子（例如stromal衍生因子-1alpha（SDF-1Alpha）（SDF-1Alpha）及其受体（例如CXCR4）在运动中起关键作用在特定转移性部位的癌细胞归巢和癌细胞的增殖。我们和其他人先前已经报道说，细胞外信号激活的转录因子NF-kappab上调了高度转移性乳腺癌细胞系中基质金属蛋白酶，尿蛋白酶型纤溶酶原激活剂和细胞因子的表达。在本报告中，我们证明了NF-kappab通过直接上调CXCR4的表达来调节乳腺癌细胞的运动。乳腺癌细胞中Kappab抑制剂（Ikappab）的过表达导致CXCR4的表达降低，并且在体外降低了SDF-1Alpha介导的迁移。将CXCR4 cDNA引入表达IKAPPAB的细胞中，恢复了SDF-1Alpha介导的迁移。电泳移动性转移测定法和瞬时转染测定法显示，NF -kappab亚基P65和P50直接与CXCR4启动子的-66至+7区域内的序列结合并激活转录。我们还表明，与培养物中生长的亲本细胞相比，在从乳腺脂肪垫异种移植物中分离出的乳腺癌细胞中，CXCR4和SDF-1Alpha介导的迁移的细胞表面表达增强了。用转移到肺部转移的癌细胞观察到CXCR4细胞表面表达和SDF-1Alpha介导的迁移。综上所述，这些结果暗示了NF-kappab在转移性乳腺癌细胞的迁移和特定器官特定的归位中。
Metastasis of cancer cells is a complex process involving multiple steps including invasion, angiogenesis, and trafficking of cancer cells through blood vessels, extravasations, organ-specific homing, and growth. While matrix metalloproteinases, urokinase- type plasminogen activator, and cytokines play a major role in invasion and angiogenesis, chemokines such as stromal derived factor-1alpha (SDF-1alpha) and their receptors such as CXCR4 are thought to play a critical role in motility, homing, and proliferation of cancer cells at specific metastatic sites. We and others have previously reported that the extracellular signal-activated transcription factor NF-kappaB up-regulates the expression of matrix metalloproteinases, urokinase- type plasminogen activator, and cytokines in highly metastatic breast cancer cell lines. In this report, we demonstrate that NF-kappaB regulates the motility of breast cancer cells by directly up-regulating the expression of CXCR4. Overexpression of the inhibitor of kappaB (IkappaB) in breast cancer cells with constitutive NF-kappaB activity resulted in reduced expression of CXCR4 and a corresponding loss of SDF-1alpha-mediated migration in vitro. Introduction of CXCR4 cDNA into IkappaB-expressing cells restored SDF-1alpha-mediated migration. Electrophoretic mobility shift assays and transient transfection assays revealed that the NF-kappaB subunits p65 and p50 bind directly to sequences within the -66 to +7 region of the CXCR4 promoter and activate transcription. We also show that the cell surface expression of CXCR4 and the SDF-1alpha-mediated migration are enhanced in breast cancer cells isolated from mammary fat pad xenografts compared with parental cells grown in culture. A further increase in CXCR4 cell surface expression and SDF-1alpha-mediated migration was observed with cancer cells that metastasized to the lungs. Taken together, these results implicate NF-kappaB in the migration and the organ-specific homing of metastatic breast cancer cells.