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Publication : WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma.

First Author  Del Mare S Year  2016
Journal  Cancer Res Volume  76
Issue  20 Pages  6107-6117
PubMed ID  27550453 Mgi Jnum  J:236247
Mgi Id  MGI:5805585 Doi  10.1158/0008-5472.CAN-16-0621
Citation  Del Mare S, et al. (2016) WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma. Cancer Res 76(20):6107-6117
abstractText  Osteosarcoma is a highly metastatic form of bone cancer in adolescents and young adults that 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 preosteoblasts (WwoxDeltaosx1) 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 WwoxDeltaosx1 mice rescued the osteogenic defect. In addition, the Wwox;p53Deltaosx1 double knockout mice developed poorly differentiated osteosarcomas that resemble human osteosarcoma in histology, location, metastatic behavior, and gene expression. Strikingly, the development of osteosarcomas in these mice was greatly accelerated compared with mice lacking p53 only. In contrast, combined WWOX and p53 inactivation in mature osteoblasts did not accelerate osteosarcomagenesis compared with 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 osteosarcoma. The Wwox;p53Deltaosx1 double knockout establishes a new osteosarcoma model with significant advancement over existing models. Cancer Res; 76(20); 6107-17. (c)2016 AACR.
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