Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, 1900 Coffey Road, 444 Veterinary Medical Academic Building, Columbus, OH, USA.
Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.
BMC Vet Res. 2020 Oct 31;16(1):415. doi: 10.1186/s12917-020-02638-3.
The 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/RESULTS: WWOX 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.
These 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.
WW 结构域氧化还原酶（WWOX）肿瘤抑制基因在人类多种实体瘤和血液系统恶性肿瘤中经常丢失。WWOX 的失调被认为在肿瘤细胞存活、DNA 损伤修复和基因组稳定性中发挥关键作用。本研究的目的是描述自发性犬肥大细胞瘤（MCT）和恶性细胞系中 WWOX 的表达，并研究 WWOX 缺失对恶性肥大细胞行为的潜在影响。
方法/结果：与正常犬骨髓培养的肥大细胞相比，原发性犬 MCT 和恶性肥大细胞系中 WWOX 的表达降低。在转化的犬肥大细胞瘤细胞系中，过表达 WWOX 或 WWOX 敲低对肥大细胞活力没有影响。在 C2 肥大细胞系中，抑制 WWOX 增强了电离辐射处理后的集落存活能力。最后，使用犬 MCT 组织微阵列对 WWOX 进行免疫组织化学染色，结果表明与低级别 MCT 相比，高级别 MCT 中 WWOX 的染色强度和染色细胞百分比降低。
这些数据表明，原发性犬 MCT 和恶性肥大细胞系中 WWOX 的表达减弱或丢失。鉴于观察到在电离辐射处理的 WWOX 缺陷型 C2 肥大细胞中集落存活能力增加，进一步研究 WWOX 及其在介导恶性肥大细胞 DNA 损伤反应中的作用是必要的。
