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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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Title: Evaluating the Role of TGFbeta and its Downstream Signaling Mediator TAZ in Canine Osteosarcoma Response to Doxorubicin
Author: Andrade, Adam
Department: Department of Biomedical Sciences
Program: Biomedical Sciences
Advisor: Viloria-Petit, Alicia
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.
URI: http://hdl.handle.net/10214/10051
Date: 2016-09
Rights: Attribution-NonCommercial-NoDerivs 2.5 Canada
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Attribution-NonCommercial-NoDerivs 2.5 Canada Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs 2.5 Canada