CXCR4 expression heterogeneity in neuroblastoma cells due to ligand-independent regulation.
CXCR4 expression heterogeneity in neuroblastoma cells due to ligand-independent regulation.
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DOI：
10.1186/1476-4598-8-126
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发表时间：
2009-12-22
期刊：
影响因子：
37.3
通讯作者：
Maris JM
中科院分区：
文献类型：
--
作者：
Carlisle AJ;Lyttle CA;Carlisle RY;Maris JM
趋化因子基质衍生因子1（SDF-1）的受体CXCR 4已被证明介导许多癌症进展所必需的过程，如肿瘤细胞增殖、转移和血管生成。为了理解CXCR 4在神经母细胞瘤（一种在超过50%的患者中呈现广泛转移的疾病）的生物学中的作用，我们筛选了10个患者来源的神经母细胞瘤细胞系的基础CXCR 4表达，并试图鉴定与肿瘤细胞表型相关的特征。所有细胞系均以不同水平表达CXCR 4 mRNA，这与流式细胞术定义的三种不同类别的CXCR 4表面表达（低、中或高）相关性良好。CXCR 4表面表达的中、高表达细胞系的动力学分析显示，受体的时间依赖性下调与细胞融合直接相关，并且与SDF 1无关。细胞裂解物显示存在多种CXCR 4同种型，其中约87、67和55 kDa的三种主要种类与高表面表达相关，45和38 kDa的两种不同种类与低至零表面表达相关。CXCR 4免疫沉淀物的Western印迹分析表明，87和67 kDa的形式是泛素化的，而其他的则不是。最后，用蛋白酶体抑制剂处理细胞导致CXCR 4表面表达下调。总之，这些数据表明，调节CXCR 4表面表达的神经母细胞瘤细胞可以发生独立的SDF-1的贡献，反对自分泌机制。此外，这些数据表明，CXCR 4的翻译后修饰，部分通过直接泛素化，可以影响CXCR 4的运输到神经母细胞瘤细胞的表面，在配体非依赖性的方式。
CXCR4, the receptor for the chemokine stromal-derived factor 1 (SDF-1), has been shown to mediate many of the processes essential for cancer progression such as tumor cell proliferation, metastasis, and angiogenesis. To understand the role of CXCR4 in the biology of neuroblastoma, a disease that presents with wide spread metastases in over 50% of patients, we screened ten patient derived-neuroblastoma cell-lines for basal CXCR4 expression and sought to identify characteristics that correlate with tumor cell phenotype. All cell lines expressed CXCR4 mRNA at variable levels, that correlated well with three distinct classes of CXCR4 surface expression (low, moderate, or high) as defined by flow cytometry. Analysis of the kinetics of CXCR4 surface expression on moderate and high expressing cell lines showed a time-dependent down-regulation of the receptor that directly correlated with cell confluency, and was independent of SDF1. Cell lysates showed the presence of multiple CXCR4 isoforms with three major species of approximately 87, 67 and 55 kDa associating with high surface expression, and two distinct species of 45 and 38 kDa correlating with low to null surface expression. Western blot analysis of CXCR4 immunoprecipitates showed that the 87 and 67 kDa forms were ubiquitinated, while the others were not. Finally, treatment of cells with a proteasome inhibitor resulted in down regulation of CXCR4 surface expression. Taken together, these data show that regulation of CXCR4 surface expression in neuroblastoma cells can occur independently of SDF-1 contribution arguing against an autocrine mechanism. Additionally these data suggest that post-translational modifications of CXCR4, in part through direct ubiquitination, can influence trafficking of CXCR4 to the surface of neuroblastoma cells in a ligand-independent manner.
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影响因子：
37.3
作者：
Fay MJ;Longo KA;Karathanasis GA;Shope DM;Mandernach CJ;Leong JR;Hicks A;Pherson K;Husain A
通讯作者：
Husain A
影响因子：
56.9
作者：
Feng, Y;Broder, CC;Berger, EA
通讯作者：
Berger, EA
DOI：
10.1073/pnas.95.16.9448
发表时间：
1998-08-04
影响因子：
11.1
作者：
Ma, Q;Jones, D;Springer, TA
通讯作者：
Springer, TA
影响因子：
4.8
作者：
Marchese, A;Benovic, JL
通讯作者：
Benovic, JL
影响因子：
11.2
作者：
Wang, Qun;Diskin, Sharon;Maris, John M.
通讯作者：
Maris, John M.