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Makii MS Dissertation_JF FINAL.pdf (5.35 MB)

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Characterization of Wwox Expression and Function in Canine Mast Cell Tumors and Malignant Mast Cell Lines

Makii, Rebecca
http://rave.ohiolink.edu/etdc/view?acc_num=osu1587715457656348

Abstract Details

2020, Master of Science, Ohio State University, Comparative and Veterinary Medicine.
Mast cell tumors (MCT) are the most common skin tumor in dogs with behavior varying from benign to aggressive, metastatic disease. While activating mutations in the receptor tyrosine kinase KIT (c-KIT) have been identified in up to 30% of high-grade MCTs, the genetic alterations driving tumorigenesis in the 70% of MCTs that do not possess c-KIT mutations remains unclear. The WW domain-containing oxidoreductase (WWOX) tumor suppressor gene is frequently lost or attenuated in many human cancers and cancer cell lines and data suggest that loss of WWOX impedes DNA damage response (DDR) and repair leading to genomic instability. The purpose of this study was to characterize WWOX expression in spontaneous canine mast MCTs and mastocytoma cell lines and begin to define the functional consequences of WWOX inactivation on mast cell viability and clonogenic survival in response to double-stranded DNA (dsDNA) damaging agents. qRT-PCR and Western blotting showed that WWOX is decreased in MC lines and primary MCTs compared to bone marrow-cultured MCs, suggesting that loss of WWOX is a frequent event in this disease. WWOX expression was assessed by immunohistochemistry in paired normal dermal MCs (N = 15), low-grade MCTs (N = 14), and high-grade MCTs (N = 5) and demonstrated that there is decreased percent of cells staining for Wwox in high-grade MCTs. To better define the functional consequences of WWOX loss on MC behavior, MCs transduced with control or WWOX lentiviral or sh-RNAs targeting WWOX were treated with ionizing radiation, and cell survival and viability were assessed by clonogenicity and MTT assays. Overexpression of WWox in the BR MC line did not alter DDR or cell viability; however, further decreasing expression of WWOX in the C2 MC line conferred a survival advantage post-irradiation. Lastly, we demonstrate validation of tissue specific WWOX knockout a mouse model to better understand the role of WWOX in normal mast cells. These findings provide insight into the functions of WWOX in MCs with the ultimate goal of identifying novel targets for therapeutic intervention.
Joelle Fenger (Advisor)
Eric Green (Committee Member)
Ryan Jennings (Committee Member)
79 p.
Veterinary Services
mast cell tumor, wwox, canine

Recommended Citations

Citations

  • Makii, R. (2020). Characterization of Wwox Expression and Function in Canine Mast Cell Tumors and Malignant Mast Cell Lines [Master's thesis, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1587715457656348

    APA Style (7th edition)

  • Makii, Rebecca. Characterization of Wwox Expression and Function in Canine Mast Cell Tumors and Malignant Mast Cell Lines. 2020. Ohio State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1587715457656348.

    MLA Style (8th edition)

  • Makii, Rebecca. "Characterization of Wwox Expression and Function in Canine Mast Cell Tumors and Malignant Mast Cell Lines." Master's thesis, Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1587715457656348

    Chicago Manual of Style (17th edition)

osu1587715457656348
209
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