Functional association of WWOX and p53 in OS

Osteosarcoma (OS) is a highly metastatic and drug resistant bone cancer lacking an effective therapy, in part due to a lack of knowledge about its molecular pathogenesis. In this study, we illuminate the mechanistic underpinning of this aggressive disease through the use of mice that are genetically deficient in the tumor suppressor Wwox in either osteoblast progenitors or mature osteoblasts. Mice in which Wwox was deleted in pre-osteoblasts (Wwox(delta)osx1 mice) were defective in osteogenesis accompanied by p53 upregulation, effects that were not observed in mice lacking Wwox in mature osteoblasts. p53 deletion in WwoxΔosx1 mice rescued this osteogenic defect. In addition, doubly mutant Wwox;p53(delta)osx1 mice developed poorly differentiated osteosarcomas that resembled human OS in histology, location, metastatic behavior and gene expression. Strikingly, osteosarcoma development in these mice was accelerated greatly compared to mice deficient only in p53. In contrast, combined WWOX and p53 inactivation in mature osteoblasts did not accelerate OS development compared to p53 inactivation alone. Our findings define a WWOX-p53 genetic network that regulates normal bone formation with disruption of this network resulting in accelerated OS development. On the basis of our studies we propose the doubly mutant Wwox;p53Δosx1 mice as an improved model for human OS.

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