Abstract
BackgroundThe WW domain-containing oxidoreductase (WWOX) tumor suppressor gene is frequently lost in a variety of solid and hematopoietic malignancies in humans. Dysregulation of WWOX has been implicated as playing a key role in tumor cell survival, DNA damage repair, and genomic stability. The purpose of this study was to characterize WWOX expression in spontaneous canine mast cell tumors (MCTs) and malignant cell lines and investigate the potential contribution of WWOX loss on malignant mast cell behavior.Methods/resultsWWOX expression is decreased in primary canine MCTs and malignant mast cell lines compared to normal canine bone marrow-cultured mast cells. In transformed canine mastocytoma cell lines, overexpression of WWOX or WWOX knockdown had no effect on mast cell viability. Inhibition of WWOX enhanced clonogenic survival following treatment with ionizing radiation in the C2 mast cell line. Lastly, immunohistochemistry for WWOX was performed using a canine MCT tissue microarray, demonstrating that WWOX staining intensity and percent of cells staining for WWOX is decreased in high-grade MCTs compared to low-grade MCTs.ConclusionsThese data suggest that WWOX expression is attenuated or lost in primary canine MCTs and malignant mast cell lines. Given the observed increase in clonogenic survival in WWOX-deficient C2 mast cells treated with ionizing radiation, further investigation of WWOX and its role in mediating the DNA damage response in malignant mast cells is warranted.
Highlights
The WW domain-containing oxidoreductase (WWOX) tumor suppressor gene is frequently lost in a variety of solid and hematopoietic malignancies in humans
WW domaincontaining oxidoreductase (WWOX) expression is frequently decreased in primary canine mast cell tumor (MCT) tissues and malignant mast cell lines The presence of genetic alterations in WWOX, largely due to loss of heterozygosity, and its reduced expression has been observed in a number of human cancers [42, 43]
Concordant with our data generated in primary MCT tissues, Real-time quantitative polymerase chain reaction (RT-qPCR) confirmed that WWOX expression is substantially decreased in canine mastocytoma cell lines when compared with normal canine Bone-marrow-cultured mast cells (BMCMC) (Fig. 1b)
Summary
The WW domain-containing oxidoreductase (WWOX) tumor suppressor gene is frequently lost in a variety of solid and hematopoietic malignancies in humans. While the role of KIT dysfunction in mast cell neoplasia has been well described, a more complete understanding of the additional molecular factors that influence malignant mast cell behavior is necessary to more effectively identify novel targets for therapeutic intervention. To this end, recent genome-wide gene expression analyses suggest that the presence of distinct subclasses of low- and high-risk MCTs exist with respect to their underlying molecular phenotypes and prognoses [12, 13]. Genome-wide DNA copy number analyses demonstrate that recurrent DNA copy number aberrations (CNAs) are associated with KIT mutation status and high histological grade, suggesting that loss or gain of genes within copy number aberrant regions may contribute to the neoplastic transformation of mast cells [14]
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