Differential roles of the Wip1–p38–p53 DNA damage response pathway in early/advanced-stage ovarian clear cell carcinomas

Abstract

Background: Ovarian clear cell carcinoma (OCCC) is one of the most lethal types of ovarian cancer. Early-stage OCCC can be cured by surgery; however, advanced-stage disease shows poor prognosis due to chemoresistance unlike the more common high-grade serous carcinoma. Methods: We explored the differential roles of the Wip1–p38–p53 DNA damage response pathway in respective early- or advanced-stage OCCC by immunohistochemistry of Wip1, phospho-p38, p53, and phospho-p53 from consecutive 143 patients. Results: High Wip1 expression correlated with positive p53 (p=0.011), which in turn correlated with low nuclear phospho-p38 expression (p=0.0094). In the early stages, positive p53 showed trends toward worse overall survival (OS) (p=0.062), whereas in the advanced stages, high Wip1 correlated with worse OS (p=0.0012). The univariate and multivariate analyses of prognostic factors indicated that high Wip1 was significant and independent for worse OS (p=0.011) in the advanced stages, but not in the early stages. Additionally, high Wip1 showed trends toward shorter treatment-free interval (TFI) in the advanced stages, but not in the early stages (p=0.083 vs. 0.93). Furthermore, high Wip1 was significantly associated with positive p53 only in the patients with shorter TFI (<6 months), but not in those with longer TFI (≥6 months) (p=0.036 vs. 0.34). Conclusions: Wip1 appears to play a crucial role for the prognosis of OCCC through chemoresistance specifically in the advanced stages, implicating that Wip1 possibly serves as a reasonable therapeutic target for improving chemoresistance and poor prognosis of advanced-stage OCCC.