DKK2 Mediates Osteolysis, Invasiveness, and Metastatic Spread in Ewing Sarcoma
DKK2 Mediates Osteolysis, Invasiveness, and Metastatic Spread in Ewing Sarcoma
复制标题
DOI：
10.1158/0008-5472.can-12-1492
复制
发表时间：
2013-01-15
期刊：
影响因子：
11.2
通讯作者：
Richter, Guenther H. S.
中科院分区：
文献类型：
--
作者：
Hauer, Kristina;Calzada-Wack, Julia;Richter, Guenther H. S.
尤文肉瘤是一种主要影响儿童和年轻人的溶骨性恶性肿瘤，其特点是早期转移至肺和骨。在这项研究中，我们发现促转移基因 DKK2 在尤文肉瘤中与相应的正常组织相比高度过度表达。通过 RNA 干扰，我们发现 DKK2 对于体外和体内原位异种移植小鼠模型中的恶性细胞生长至关重要。对两种环境中侵袭潜力的分析表明，DKK2 表达与尤文肉瘤侵袭性密切相关，这可能是由 DKK 效应基质金属蛋白酶 1 (MMP1) 介导的。此外，基因表达分析确定了 DKK2 能够差异调节 CXCR4、PTHrP、RUNX2 和 TGF beta 1 等基因，这些基因与骨组织中癌细胞的归巢、侵袭和生长相关，以及对骨质溶解重要的基因，包括 HIF1 α、JAG1、IL6 和 VEGF。 DKK2 在体内促进骨浸润和骨溶解，进一步分析将 DKK2 定义为骨性恶性肿瘤的关键因素。有趣的是，在尤文肉瘤细胞中，DKK2 抑制同时增加了神经元分化的潜力，同时减少了软骨形成和成骨分化。我们的结果提供了强有力的证据，表明 DKK2 在尤文肉瘤侵袭和骨溶解以及尤文肉瘤细胞的差异表型中发挥着关键作用。癌症研究； 73(2)； 967-77。 (c) 2012 年 AACR。
Ewing sarcoma, an osteolytic malignancy that mainly affects children and young adults, is characterized by early metastasis to lung and bone. In this study, we identified the pro-metastatic gene DKK2 as a highly overexpressed gene in Ewing sarcoma compared with corresponding normal tissues. Using RNA interference, we showed that DKK2 was critical for malignant cell outgrowth in vitro and in an orthotopic xenograft mouse model in vivo. Analysis of invasion potential in both settings revealed a strong correlation of DKK2 expression to Ewing sarcoma invasiveness that may be mediated by the DKK effector matrix metalloproteinase 1 (MMP1). Furthermore, gene expression analyses established the ability of DKK2 to differentially regulate genes such as CXCR4, PTHrP, RUNX2, and TGF beta 1 that are associated with homing, invasion, and growth of cancer cells in bone tissue as well as genes important for osteolysis, including HIF1 alpha, JAG1, IL6, and VEGF. DKK2 promoted bone infiltration and osteolysis in vivo and further analyses defined DKK2 as a key factor in osteotropic malignancy. Interestingly, in Ewing sarcoma cells, DKK2 suppression simultaneously increased the potential for neuronal differentiation while decreasing chondrogenic and osteogenic differentiation. Our results provide strong evidence that DKK2 is a key player in Ewing sarcoma invasion and osteolysis and also in the differential phenotype of Ewing sarcoma cells. Cancer Res; 73(2); 967-77. (c) 2012 AACR.