title: ΔNp63 mediates cellular survival and metastasis in canine osteosarcoma.
abstract: p63 is a structural homolog within the 53 family encoding two isoforms, ΔNp63 and TAp63. The oncogenic activity of ΔNp63 has been demonstrated in multiple cancers, however the underlying mechanisms that contribute to tumorigenesis are poorly characterized. Osteosarcoma (OSA) is the most common primary bone tumor in dogs, exhibiting clinical behavior and molecular biology essentially identical to its human counterpart. The purpose of this study was to evaluate the potential contribution of ΔNp63 to the biology of canine OSA. As demonstrated by qRT-PCR, nearly all canine OSA cell lines and tissues overexpressed ΔNp63 relative to normal control osteoblasts. Inhibition of ΔNp63 by RNAi selectively induced apoptosis in the OSA cell lines overexpressing ΔNp63. Knockdown of ΔNp63 upregulated expression of the proapoptotic Bcl-2 family members Puma and Noxa independent of p53. However the effects of ΔNp63 required transactivating isoforms of p73, suggesting that ΔNp63 promotes survival in OSA by repressing p73-dependent apoptosis. In addition, ΔNp63 modulated angiogenesis and invasion through its effects on VEGF-A and IL-8 expression, and STAT3 phosphorylation. Lastly, the capacity of canine OSA cell lines to form pulmonary metastasis was directly related to expression levels of ΔNp63 in a murine model of metastatic OSA. Together, these data demonstrate that ΔNp63 inhibits apoptosis and promotes metastasis, supporting continued evaluation of this oncogene as a therapeutic target in both human and canine OSA.
authors.affiliation: Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
authors.forename: Maren
authors.initials: M
authors.lastname: Cam
authors.affiliation: Department of Veterinary Clinical Sciences and Biosciences, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Gardner
authors.affiliation: Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.|Department of Pediatrics, The Ohio State University College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Roberts
authors.affiliation: Department of Veterinary Clinical Sciences and Biosciences, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Joelle M
authors.initials: JM
authors.lastname: Fenger
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Denis C
authors.initials: DC
authors.lastname: Guttridge
authors.affiliation: Department of Veterinary Clinical Sciences and Biosciences, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: London
authors.affiliation: Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.|Department of Pediatrics, The Ohio State University College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Hakan
authors.initials: H
authors.lastname: Cam
mesh_terms: D000818:Animals; D017209:Apoptosis; D001859:Bone Neoplasms / Q000473:pathology* / Q000662:veterinary; D045744:Cell Line, Tumor; D002470:Cell Survival; D004285:Dogs; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D016209:Interleukin-8 / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology* / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology; D010006:Osteoblasts; D012516:Osteosarcoma / Q000473:pathology* / Q000662:veterinary; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012513:Sarcoma, Experimental / Q000473:pathology* / Q000556:secondary; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000072160:Tumor Protein p73 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D016209:Interleukin-8; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A
keywords: canine; deltaNp63; metastasis; osteosarcoma; p53 family member