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?Np63 mediates cellular survival and metastasis in canine osteosarcoma.

ABSTRACT: p63 is a structural homolog within the 53 family encoding two isoforms, ?Np63 and TAp63. The oncogenic activity of ?Np63 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 ?Np63 to the biology of canine OSA. As demonstrated by qRT-PCR, nearly all canine OSA cell lines and tissues overexpressed ?Np63 relative to normal control osteoblasts. Inhibition of ?Np63 by RNAi selectively induced apoptosis in the OSA cell lines overexpressing ?Np63. Knockdown of ?Np63 upregulated expression of the proapoptotic Bcl-2 family members Puma and Noxa independent of p53. However the effects of ?Np63 required transactivating isoforms of p73, suggesting that ?Np63 promotes survival in OSA by repressing p73-dependent apoptosis. In addition, ?Np63 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 ?Np63 in a murine model of metastatic OSA. Together, these data demonstrate that ?Np63 inhibits apoptosis and promotes metastasis, supporting continued evaluation of this oncogene as a therapeutic target in both human and canine OSA.

SUBMITTER: Cam M

PROVIDER: S-EPMC5217036 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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ΔNp63 mediates cellular survival and metastasis in canine osteosarcoma.

Cam Maren M Gardner Heather L HL Roberts Ryan D RD Fenger Joelle M JM Guttridge Denis C DC London Cheryl A CA Cam Hakan H

Oncotarget 20160701 30

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 ...[more]

PMID: 27391430

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Project description:BackgroundGene expression profiling of spontaneous tumors in the dog offers a unique translational opportunity to identify prognostic biomarkers and signaling pathways that are common to both canine and human. Osteosarcoma (OS) accounts for approximately 80% of all malignant bone tumors in the dog. Canine OS are highly comparable with their human counterpart with respect to histology, high metastatic rate and poor long-term survival. This study investigates the prognostic gene profile among thirty-two primary canine OS using canine specific cDNA microarrays representing 20,313 genes to identify genes and cellular signaling pathways associated with survival. This, the first report of its kind in dogs with OS, also demonstrates the advantages of cross-species comparison with human OS.ResultsThe 32 tumors were classified into two prognostic groups based on survival time (ST). They were defined as short survivors (dogs with poor prognosis: surviving fewer than 6 months) and long survivors (dogs with better prognosis: surviving 6 months or longer). Fifty-one transcripts were found to be differentially expressed, with common upregulation of these genes in the short survivors. The overexpressed genes in short survivors are associated with possible roles in proliferation, drug resistance or metastasis. Several deregulated pathways identified in the present study, including Wnt signaling, Integrin signaling and Chemokine/cytokine signaling are comparable to the pathway analysis conducted on human OS gene profiles, emphasizing the value of the dog as an excellent model for humans.ConclusionA molecular-based method for discrimination of outcome for short and long survivors is useful for future prognostic stratification at initial diagnosis, where genes and pathways associated with cell cycle/proliferation, drug resistance and metastasis could be potential targets for diagnosis and therapy. The similarities between human and canine OS makes the dog a suitable pre-clinical model for future 'novel' therapeutic approaches where the current research has provided new insights on prognostic genes, molecular pathways and mechanisms involved in OS pathogenesis and disease progression.

Dataset Information

?Np63 mediates cellular survival and metastasis in canine osteosarcoma.

Publications

ΔNp63 mediates cellular survival and metastasis in canine osteosarcoma.

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