Overexpression of Dock180 in ovarian carcinomas

Abstract

Background: Ovarian carcinoma is the most lethal gynecological malignancy. Although improvement in survival rate has been found for patients with advanced disease, relapse and mortality rates are still high due to the development of drug resistance and poor understanding of the mechanisms of disease progression. Identifying novel therapeutic targets for ovarian carcinoma is valuable with a view to improve the long-term survival rate. Dedicator of cytokinesis I (Dock180) superfamily of proteins was identified as novel, unconventional guanine nucleotide exchange factors (GEF) for Rho GTPases, which are important regulators for cytoskeleton organization, and may thus be essential for cancer progression. The Dock180 family members play essential roles in various biological processes including cell migration, invasion and engulfment of apoptotic cells. Dock180 has recently been shown to stimulate human glioma cell migration and invasion but its role in ovarian carcinomas has not been investigated. Methods: In this study, differential expression of Dock180 in 198 clinical samples of ovarian tumors including 10 benign cystadenomas, 18 borderline tumors, 110 carcinomas of different histological subtypes and 60 metastatic foci of ovarian carcinomas was evaluated by immunohistochemistry. By real-time PCR and immunoblotting, DOCK180 expression was also assessed in cell-lines of human normal ovarian epithelium (HOSE-11-12 and HOSE-17-1) and human ovarian carcinoma (OVCAR-3, OVCA420, OVCA433, PAI and OC316). Results: Carcinomas and borderline tumors displayed a significantly higher level of cytoplasmic Dock180 expression than the benign cystadenomas (P<0.002). We also demonstrated a significant association between increased expression of Dock180 and metastatic carcinomas (P<0.0001), high grade cancers (P<0.005) and serous histological subtypes (P<0.005). Patients with higher Dock180 expression in cancer cells had lower overall survival rate (P<0.05) and disease-free survival rate (P<0.05) than those with lower Dock180 expression. Interestingly, moderate to strong nuclear staining of Dock180 was also observed, implicating that Dock180 may have functions in both the nucleus and the cytoplasm. Real-time PCR showed significantly elevated Dock180 expression in ovarian carcinoma cell lines as compared to normal ovarian epithelium cell lines. Immunoblotting also demonstrated increased Dock180 expression in ovarian carcinoma cell lines. Conclusion: Based on our findings, Dock180 overexpression was correlated with malignant progression of ovarian tumor as well as overall and disease-free survival of patients with ovarian carcinoma. Dock180 is likely to act as a prognostic marker and therapeutic target in ovarian carcinoma.