Regulation of expression of stromal-derived factor-1 receptors: CXCR4 and CXCR7 in human rhabdomyosarcomas.
Regulation of expression of stromal-derived factor-1 receptors: CXCR4 and CXCR7 in human rhabdomyosarcomas.
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DOI：
10.1158/1541-7786.mcr-09-0259
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发表时间：
2010-01
期刊：
影响因子：
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通讯作者：
Ratajczak MZ
中科院分区：
文献类型：
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作者：
Tarnowski M;Grymula K;Reca R;Jankowski K;Maksym R;Tarnowska J;Przybylski G;Barr FG;Kucia M;Ratajczak MZ
横纹肌肉瘤（RMS）表达CXCR 4和CXCR 7受体，其结合促转移α-趋化因子基质衍生因子-1。在本报告中，我们分析了两种启动子在转移性较低的人胚胎RMS细胞系（RD）和转移性较高的肺泡样RMS（用配对盒基因3/叉头同源物-PAX 3-FKHR融合基因转导的RD细胞）模型中的活性。首先，CXCR 4在RD上几乎检测不到，并且在RD/PAX 3-FKHR细胞上上调。相反，RD上高表达的CXCR 7在RD/PAX 3-FKHR细胞中下调。接下来，启动子缺失和突变研究表明：i）RD和RD/PAX 3-FKHR细胞中CXCR 4的表达需要核呼吸因子-1（NRF-1）结合位点，ii）NRF-1与PAX 3-FKHR的直接相互作用额外上调，而CXCR 7启动子活性需要近端核因子-κ B（NF-κB）结合基序。在阻断NRF-1和NF-κB后，这些因子对CXCR 4和CXCR 7启动子活性的需求得到了额外的支持。此外，PAX 3-FKHR+ RMS细胞中的CXCR 4表达似乎增强，因为PAX 3-FKHR和NRF-1蛋白在启动子近端部分的相互作用阻止转录负调节因子YY 1接近其结合位点。最后，虽然缺氧增强RD细胞上的CXCR 4和CXCR 7启动子活性和受体表达，但它抑制RD/PAX 3-FKHR细胞中的CXCR 7表达。总之，SDF-1结合受体CXCR 4和CXCR 7在RMS细胞中受到不同的调节。通过PAX 3-FKHR或缺氧上调CXCR 4和下调CXCR 7表达可能使SDF-1更好地与CXCR 4受体结合，从而增加RMS运动性。
Rhabdomyosarcomas (RMS) express CXCR4 and CXCR7 receptors that bind prometastatic α-chemokine stromal derived factor-1. In this report we analyzed the activity of both promoters in a model of less metastatic human embryonal-RMS cell line (RD) and more metastatic alveolar-like RMS (RD cells transduced with Paired box gene 3/forkhead homolog - PAX3-FKHR fusion gene). First, CXCR4 is barely detectable on RD and becomes upregulated on RD/PAX3-FKHR cells. In contrast, CXCR7 highly expressed on RD becomes downregulated in RD/PAX3-FKHR cells. Next, promoter deletion and mutation studies revealed that while: i) expression of CXCR4 in RD and RD/PAX3-FKHR cells required nuclear respiratory factor-1 (NRF-1) binding site and ii) was additionally upregulated by direct interaction of NRF-1 with PAX3-FKHR, CXCR7 promoter activity required a proximal nuclear factor-kappa B (NF-κB) binding motif. The requirement of these factors for CXCR4 and CXCR7 promoter activities was additionally supported after blocking NRF-1 and NF-κB. Furthermore, CXCR4 expression in PAX3-FKHR+ RMS cells seems to be enhanced because of the interaction of PAX3-FKHR and NRF-1 proteins in the proximal part of the promoter that prevents access of the negative regulator of transcription YY1 to its binding site. Finally, while hypoxia enhances CXCR4 and CXCR7 promoter activity and receptor expression on RD cells, it inhibits CXCR7 expression in RD/PAX3-FKHR cells. In conclusion, SDF-1 binding receptors CXCR4 and CXCR7 are differently regulated in RMS cells. The upregulation of CXCR4 and downregulation of CXCR7 expression by PAX3-FKHR or hypoxia may give SDF-1 an advantage to better engage the CXCR4 receptor, thus increasing RMS motility.