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Cdc7 kinase is a predictor of survival and a novel therapeutic target in epithelial ovarian carcinoma. | LitMetric

AI Article Synopsis

  • The study investigates Cdc7 kinase as a potential prognostic biomarker and therapeutic target in epithelial ovarian carcinoma, addressing the lack of such biomarkers in this complex disease.
  • The analysis of 143 ovarian cancer cases demonstrated that high Cdc7 levels correlate with worse outcomes, including poor tumor differentiation, advanced clinical stage, and increased genomic instability.
  • Downregulating Cdc7 in ovarian cancer cell lines resulted in significant cell death, suggesting Cdc7’s potential as a target for new cancer therapies and a predictor of patient survival.

Article Abstract

Purpose: 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.

Experimental Design: 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.

Results: 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.

Conclusions: 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.

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Source
http://dx.doi.org/10.1158/1078-0432.CCR-08-1276DOI Listing

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