WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma.
WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma.
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DOI：
10.1158/0008-5472.can-16-0621
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发表时间：
2016-10-15
期刊：
影响因子：
11.2
通讯作者：
Aqeilan RI
中科院分区：
文献类型：
--
作者：
Del Mare S;Husanie H;Iancu O;Abu-Odeh M;Evangelou K;Lovat F;Volinia S;Gordon J;Amir G;Stein J;Stein GS;Croce CM;Gorgoulis V;Lian JB;Aqeilan RI
骨肉瘤（OS）是青少年和年轻人中的一种高转移性骨癌，对现有治疗具有耐药性。由于对骨质疏松症发生机制的认识非常有限，有效治疗的发展受到阻碍。在这里，我们使用基因工程小鼠来研究在成骨祖细胞或成熟成骨细胞中选择性删除肿瘤抑制因子Wwox的影响。在前成骨细胞中条件性缺失Wwox的小鼠（WwoxΔ osx 1）显示出严重的骨生成抑制，伴有p53上调，在成熟成骨细胞中缺乏Wwox的小鼠中未观察到这种效应。WwoxΔ osx 1小鼠中p53的缺失挽救了成骨缺陷。此外，Wwox; p53Δ osx 1双基因敲除小鼠发生低分化骨肉瘤，在组织学、位置、转移行为和基因表达方面与人类OS相似。引人注目的是，与仅缺乏p53的小鼠相比，这些小鼠中骨肉瘤的发展大大加速。与此相反，在成熟成骨细胞中，WWOX和p53失活的组合与单独p53失活相比并没有加速骨肉瘤的发生。这些发现提供了证据表明，WWOX-p53网络调节正常的骨形成，并且在骨祖细胞中该网络的破坏导致加速的OS。Wwox;p53Δ osx 1双敲除建立了一种新的OS模型，与现有模型相比具有显著的进步。
Osteosarcoma (OS) is a highly metastatic form of bone cancer in adolescents and young adults which is resistant to existing treatments. Development of an effective therapy has been hindered by very limited understanding of the mechanisms of osteosarcomagenesis. Here, we used genetically engineered mice to investigate the effects of deleting the tumor suppressor Wwox selectively in either osteoblast progenitors or mature osteoblasts. Mice with conditional deletion of Wwox in pre-osteoblasts (WwoxΔosx1) displayed a severe inhibition of osteogenesis accompanied by p53 upregulation, effects that were not observed in mice lacking Wwox in mature osteoblasts. Deletion of p53 in WwoxΔosx1 mice rescued the osteogenic defect. In addition, the Wwox;p53Δosx1 double knockout mice developed poorly differentiated osteosarcomas that resemble human OS in histology, location, metastatic behavior, and gene expression. Strikingly, the development of osteosarcomas in these mice was greatly accelerated compared to mice lacking p53 only. In contrast, combined WWOX and p53 inactivation in mature osteoblasts did not accelerate osteosarcomagenesis compared to p53 inactivation alone. These findings provide evidence that a WWOX-p53 network regulates normal bone formation and that disruption of this network in osteoprogenitors results in accelerated OS. The Wwox;p53Δosx1 double knockout establishes a new OS model with significant advancement over existing models.