Τίτλος:
WWOX and p53 dysregulation synergize to drive the development of osteosarcoma
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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 (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 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;p53Δosx1 double knockout establishes a new osteosarcoma model with significant advancement over existing models. ©2016 AACR.
Συγγραφείς:
Del Mare, S.
Husanie, H.
Iancu, O.
Abu-Odeh, M.
Evangelou, K.
Lovat, F.
Volinia, S.
Gordon, J.
Amir, G.
Stein, J.
Stein, G.S.
Croce, C.M.
Gorgoulis, V.
Lian, J.B.
Aqeilan, R.I.
Περιοδικό:
Clinical Cancer Research
Εκδότης:
American Association for Cancer Research Inc.
Λέξεις-κλειδιά:
transcription factor RUNX2; oxidoreductase; peptide fragment; procollagen; procollagen Type I N-terminal peptide; protein p53; RUNX2 protein, human; TP53 protein, human; transcription factor RUNX2; tumor suppressor protein; WWOX protein, human, animal cell; animal experiment; animal model; animal tissue; Article; bone development; carcinogenesis; cell differentiation; controlled study; DNA damage response; gene; gene deletion; gene expression; gene inactivation; gene mutation; human; human tissue; immunohistochemistry; major clinical study; metastasis; mouse; nonhuman; osteoblast; osteosarcoma; priority journal; transcriptomics; tumor differentiation; tumor suppressor gene; upregulation; WWOX gene; animal; blood; Bone Neoplasms; cell lineage; gene expression profiling; genetics; knockout mouse; osteosarcoma; physiology, Animals; Bone Neoplasms; Cell Differentiation; Cell Lineage; Core Binding Factor Alpha 1 Subunit; Gene Expression Profiling; Humans; Mice; Mice, Knockout; Osteoblasts; Osteogenesis; Osteosarcoma; Oxidoreductases; Peptide Fragments; Procollagen; Tumor Suppressor Protein p53; Tumor Suppressor Proteins
DOI:
10.1158/0008-5472.CAN-16-0621
