Abstract
There is a lack of prognostic and predictive biomarkers in epithelial ovarian carcinoma, and the targeting of oncogenic signaling pathways has had limited impact on patient survival in this highly heterogeneous disease. The origin licensing machinery, which renders chromosomes competent for DNA replication, acts as a convergence point for upstream signaling pathways. We tested the hypothesis that Cdc7 kinase, a core component of the licensing machinery, is predictive of clinical outcome and may constitute a novel therapeutic target in epithelial ovarian carcinoma. A total of 143 cases of ovarian cancer and 5 cases of normal ovary were analyzed for Cdc7 protein expression dynamics and clinicopathologic features. To assess the therapeutic potential of Cdc7, expression was down-regulated by RNA interference in SKOV-3 and Caov-3 ovarian cancer cells. Increased Cdc7 protein levels were significantly associated with arrested tumor differentiation (P = 0.004), advanced clinical stage (P = 0.01), genomic instability (P < 0.001), and accelerated cell cycle progression. Multivariate analysis shows that Cdc7 predicts disease-free survival independent of patient age, tumor grade and stage (hazard ratio, 2.03; confidence interval, 1.53-2.68; P < 0.001), with the hazard ratio for relapse increasing to 10.90 (confidence interval, 4.07-29.17) for the stages 3 to 4/upper Cdc7 tertile group relative to stages 1 to 2/lower Cdc7 tertile tumors. In SKOV-3 and Caov-3 cells, Cdc7 siRNA knockdown triggered high levels of apoptosis, whereas untransformed cells arrest in G(1) phase and remain viable. Our findings show that Cdc7 kinase predicts survival and is a potent anticancer target in epithelial ovarian carcinoma, highlighting its potential as a predictor of susceptibility to small molecule kinase inhibitors currently in development.
Highlights
There is a lack of prognostic and predictive biomarkers in epithelial ovarian carcinoma, and the targeting of oncogenic signaling pathways has had limited impact on patient survival in this highly heterogeneous disease
We analyzed the expression dynamics of Cdc7 in diagnostic tumor specimens from a published cohort of 143 epithelial ovarian carcinoma cases [17] and in 5 cases of normal ovarian tissue
We found a significant positive correlation between Cdc7 expression and the geminin/ Ki67 ratio (Spearman correlation coefficient, 0.23; 95% confidence intervals (95% CI), 0.07-0.38; P = 0.006), indicating that increased Cdc7 expression is coupled to accelerated cell cycle progression observed in advanced-stage epithelial ovarian carcinoma, consistent with the rate-limiting role of Cdc7 for S phase entry and progression
Summary
There is a lack of prognostic and predictive biomarkers in epithelial ovarian carcinoma, and the targeting of oncogenic signaling pathways has had limited impact on patient survival in this highly heterogeneous disease. Cdc down-regulation by RNA interference in two ovarian cancer cell lines triggered apoptosis, suggesting Cdc as a potent anticancer target in epithelial ovarian carcinoma and highlighting its potential as a predictor of therapeutic response to small molecule kinase inhibitors. Mcm have been identified as powerful biomarkers for cancer detection and prognostication [11, 15], and combined analysis of minichromosome maintenance protein expression dynamics and biomarkers of S-G2-M progression (geminin, Aurora A, Plk, and the Aurora kinase substrate Histone H3) allows determination of tumor cell cycle kinetics [11, 16, 17] This cell cycle biomarker panel allows out-of-cycle quiescent (G0), differentiated, or senescent cells to be distinguished from those residing in-cycle, and, can assign cells to G1, S-G2 and M phase of the cell division cycle It has been suggested that inhibition of origin firing through targeting Cdc provokes a tumor cell – specific apoptotic response [20]
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