Abstract
PurposeEpithelial ovarian cancer has the highest mortality rate of all gynecological malignancies. We have shown that high RAN expression strongly correlates with high-grade and poor patient survival in epithelial ovarian cancer. However, as RAN is a small GTPase involved in two main biological functions, nucleo-cytoplasmic transport and mitosis, it is still unknown which of these functions associate with poor prognosis.MethodsTo examine the biomarker value of RAN network components in serous epithelial ovarian cancer, protein expression of six specific RAN partners was analyzed by immunohistochemistry using a tissue microarray representing 143 patients associated with clinical parameters. The RAN GDP/GTP cycle was evaluated by the expression of RANBP1 and RCC1, the mitotic function by TPX2 and IMPβ, and the nucleo-cytoplasmic trafficking function by XPO7, XPOT and IMPβ.ResultsBased on Kaplan-Meier analyses, RAN, cytoplasmic XPO7 and TPX2 were significantly associated with poor overall patient survival, and RAN and TPX2 were associated with lower disease free survival in patients with high-grade serous carcinoma. Cox regression analysis revealed that RAN and TPX2 expression were independent prognostic factors for both overall and disease free survival, and that cytoplasmic XPO7 expression was a prognostic factor for overall patient survival.ConclusionsIn this systematic study, we show that RAN and two protein partners involved in its nucleo-cytoplasmic and mitotic functions (XPO7 and TPX2, respectively) can be used as biomarkers to stratify patients based on prognosis. In particular, we reported for the first time the clinical relevance of the exportin XPO7 and showed that TPX2 expression had the strongest prognostic value. These findings suggest that protein partners in each of RAN’s functions can discriminate between different outcomes in high-grade serous epithelial ovarian cancer patients. Furthermore, these proteins point to cellular processes that may ultimately be targeted to improve the survival in serous epithelial ovarian cancer.
Highlights
Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic malignancies in North America [1] and worldwide
To determine if any of the partners of RAN are implicated in the biology of EOC, we performed an IHC analysis using a Tissue Microarray (TMA) containing a total of 286 cores of cancer specimens representing 143 patients
Expression of RAN (Figure 1A–C), RANBP1 (Figure 1D–F) and importin b (IMPb) (Figure 1J–L) were localized to both the cytoplasm and the nucleus, signal quantification focused exclusively on the cytoplasm based on its higher expression in this cellular compartment
Summary
Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic malignancies in North America [1] and worldwide. This is attributed to the asymptomatic nature of the disease implying a late diagnosis with a five-year survival rate at 30% [2,3]. Patients with HG serous carcinoma have a poor prognosis with survival at five-years of less than 40% [11] Research into these two distinct diseases, LG and HG serous EOC, would provide a better understanding of ovarian cancer biology and help improve clinical outcomes. Biomarker discovery discriminating HG serous EOC patients having good or poor prognosis may contribute to patient therapeutic stratification and may increase overall survival
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