The CCL6 chemokine is differentially regulated by c-Myc and L-Myc, and promotes tumorigenesis and metastasis.
The CCL6 chemokine is differentially regulated by c-Myc and L-Myc, and promotes tumorigenesis and metastasis.
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发表时间：
2003-06
期刊：
影响因子：
11.2
通讯作者：
Fenghua Yi;R. Jaffe;E. Prochownik
中科院分区：
文献类型：
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作者：
Fenghua Yi;R. Jaffe;E. Prochownik
在白细胞介素3依赖的32D骨髓细胞中，CCL6趋化因子基因被确定为L-Myc癌蛋白的直接阳性靶点。缺乏转录抑制所需的NH(2)末端结构域区域（c-MycDeltaMBII）的c-Myc突变形式也上调了CCL6。染色质免疫沉淀显示，L-Myc、c-MycDeltaMBII和全长c-Myc都结合了CCL6启动子，尽管后者在转录上调中不活跃。外源添加CCL6可诱导部分细胞明显凋亡。然而，在32D细胞中，c-Myc和CCL6的共表达消除了对白细胞介素3的依赖性，并产生了高度致白血病的表型。在两种实体瘤模型中，CCL6过表达也加速了肿瘤生长，和/或增强了局部和转移性扩散，并伴有肿瘤被膜和邻近正常组织的显著凋亡。我们的研究结果表明，CCL6可以是Myc癌蛋白的阳性或阴性靶标。趋化因子可能通过减轻肿瘤对生长因子的依赖和促进局部组织凋亡的侵袭性来改变肿瘤行为。
The CCL6 chemokine gene was identified as a direct positive target of the L-Myc oncoprotein in interleukin 3-dependent 32D myeloid cells. A mutant form of c-Myc, lacking a region of the NH(2)-terminal domain necessary for transcriptional repression (c-MycDeltaMBII), also up-regulated CCL6. Chromatin immunoprecipitation showed that L-Myc, c-MycDeltaMBII, and full-length c-Myc all bound the CCL6 promoter, although the latter was inactive in transcriptional up-regulation. Exogenously added CCL6 induced marked apoptosis in some cell types. However, in 32D cells, the coexpression of c-Myc and CCL6 abrogated interleukin 3 dependence and produced a highly leukemogenic phenotype. In two solid tumor models, CCL6 overexpression also accelerated tumor growth, and/or enhanced local and metastatic spread in association with marked apoptosis of the tumor capsule and adjacent normal tissues. Our results show that CCL6 can be either a positive or negative target for Myc oncoproteins. The chemokine may alter tumor behavior by relieving its growth factor dependency and by promoting invasiveness as a result of local tissue apoptosis.