Deregulation of IKBKE Is Associated with Tumor Progression, Poor Prognosis, and Cisplatin Resistance in Ovarian Cancer

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American Society for Investigative Pathology

RESUMO

I-kappa-B kinase e (IKBKE; IKKε) has been recently identified as a breast cancer oncogene, and its alteration appears to be an early event in breast cancer development. In this study, we demonstrated that IKKε is frequently overexpressed and activated in human ovarian cancer cell lines and primary tumors. Of 96 ovarian cancer specimens examined, 63 exhibited elevated levels of IKKε. Furthermore, alterations of IKKε were associated with late-stage and high-grade tumors, suggesting a role of IKKε in ovarian tumor progression rather than in tumor initiation. Overall survival in patients with elevated levels of IKKε was significantly lower than patients whose tumors expressed normal levels of IKKε. Moreover, both early and late-stage tumors that overexpressed IKKε conferred a poor prognosis, as compared with those that did not possess elevated IKKε levels. Notably, overexpression of IKKε rendered cells resistant to cisplatin, whereas knockdown of IKKε overcame cisplatin resistance in both A2780CP and C13 cells, which express high levels of endogenous IKKε. Therefore, these data demonstrate for the first time that deregulation of IKKε is a highly recurrent event in human ovarian cancer and could play a pivotal role in tumor progression and cisplatin resistance. IKKε could also serve as a prognostic marker and potential therapeutic target for this malignancy.

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