DYRK2 regulates epithelial-mesenchymal-transition and chemosensitivity through Snail degradation in ovarian serous adenocarcinoma
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Epithelial-mesenchymal-transition (EMT) plays essential roles in ovarian cancer invasion, metastasis, and drug resistance. A hallmark of EMT is the loss of E-cadherin, which is regulated by Snail. Recently, it was shown that dual-specificity tyrosine-regulated kinase 2 (DYRK2) controls Snail degradation in breast cancer. The aim of this study is to clarify whether DYRK2 regulates EMT through Snail degradation in ovarian serous adenocarcinoma (SA). Expression of DYRK2 and Snail in two pairs of cisplatin-resistant and the original cisplatin-sensitive ovarian cancer cell line were analyzed by immunoblotting and real-time RT-PCR analysis. Morphological change, invasion ability, and chemosensitivity were evaluated by using DYRK2 stable knockdown cell line in 2008 (2008 shDYRK2). Immunohistochemical analyses for DYRK2 and Snail were performed with surgical specimens. The correlations between the expression of these proteins and the clinicopathological parameters, including prognosis, were determined. Moreover, we conducted a hypodermic administration test in nude mice and examined reproductive and cisplatin response activities. DYRK2 protein expression was posttranslationally reduced in cisplatin-resistant SA cell lines. 2008 shDYRK2 showed mesenchymal phenotype and resistant to cisplatin. Immunohistochemistry demonstrated that DYRK2 expression inversely correlated with Snail expression, and reduced expression of DYRK2 was associated with shorter overall survival in SA. DYRK2 may regulate EMT through Snail degradation in ovarian SA and might be a predictive marker for a favorable prognosis in the treatment of this cancer.
Key wordsOvarian cancer DYRK2 Snail EMT Cisplatin Chemosensitivity
Ovarian serous adenocarcinoma
Dual-specificity tyrosine-regulated kinase 2
Glycogen synthase kinase-3β
The International Federation of Gynecology and Obstetrics
This work was supported by grants from the Japan Society for the Promotion of Science, the Jikei University Graduate Research Fund, the Jikei University Research Fund, Takeda Science Foundation, the Naito Foundation, Project Mirai Cancer Research Grants, and the Vehicle Racing Commemorative Foundation.
Conflicts of interest
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