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Evaluating the Role of TGFbeta and its Downstream Signaling Mediator TAZ in Canine Osteosarcoma Response to Doxorubicin

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dc.contributor.advisor Viloria-Petit, Alicia
dc.contributor.author Andrade, Adam
dc.date.accessioned 2016-10-13T17:55:38Z
dc.date.available 2016-10-13T17:55:38Z
dc.date.copyright 2016-09
dc.date.created 2016-09-21
dc.date.issued 2016-10-13
dc.identifier.uri http://hdl.handle.net/10214/10051
dc.description.abstract Osteosarcoma (OSA) is the most common bone tumor in dogs. Metastatic canine OSA is resistant to chemotherapy and is responsible for patient mortality. OSA metastasis and chemoresistance mechanisms are generally unknown. Transforming growth factor-β (TGFβ) is a highly conserved cytokine with roles in bone development, bone disorders, cancer metastasis and chemoresistance. The action of TGFβ is carried out through SMAD transcription factors, which work in conjunction with TAZ to alter gene expression. TAZ is a highly conserved transcriptional coactivator and an integral part of the Hippo pathway controlling organ size, proliferation and differentiation, as well as bone mass and osteoblastogenesis. TAZ has been shown to mediate stem cell self-renewal capacity and cancer metastasis. I hypothesized that the TGFβ-TAZ signaling axis mediates OSA progression and chemoresistance. To demonstrate this, I assessed the effect of TGFβ on doxorubicin response, and together in connection with TAZ expression, in a panel of canine OSA cell lines, namely JL-31, JL-75 and JL-78. All cell lines used expressed TGFβRI and TGFβRII. TGFβ1 induced a dose and time-dependent effect on PSMAD2, TAZ and SNAIL-1 expression in JL-75, JL-78 and JL-31 cell lines as assessed by Western blotting. Analysis of malignancy genes via qRT-PCR indicated a time dependent increase in TAZ, SNAIL-1, SNAIL-2 (Slug) and RUNX2 genes in the OSA cell lines studied. Clonogenic survival of JL-78 and JL-31 cells in response to doxorubicin was reduced after TAZ was knocked down with siRNA only when the drug was combined with TGFβ1. The results indicate that TAZ is involved in doxorubicin resistance, downstream of TGFβ, and that TGFβ1 promotes the upregulation of genes associated with malignancy in OSA. Thus, TAZ offers potential as a novel therapeutic target for sensitizing OSA cells to doxorubicin treatment. en_US
dc.description.sponsorship OVC Fellowship, Pet Trust en_US
dc.language.iso en en_US
dc.rights Attribution-NonCommercial-NoDerivs 2.5 Canada *
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/2.5/ca/ *
dc.subject Osteosarcoma en_US
dc.subject Doxorubicin en_US
dc.subject TGFbeta en_US
dc.subject TAZ en_US
dc.subject Canine en_US
dc.subject Chemoresistance en_US
dc.title Evaluating the Role of TGFbeta and its Downstream Signaling Mediator TAZ in Canine Osteosarcoma Response to Doxorubicin en_US
dc.type Thesis en_US
dc.degree.programme Biomedical Sciences en_US
dc.degree.name Master of Science en_US
dc.degree.department Department of Biomedical Sciences en_US
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