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Expression of cIAP1, a Target for 11q22 Amplification, Correlates with Resistance of Cervical Cancers to Radiotherapy¹

Department of Molecular Cytogenetics, Medical Research Institute [I. I, A. H., J. I.] and Molecular Diagnosis and Therapeutics, Department of Oral Restitution, Graduate School [M. M.], Tokyo Medical & Dental University, Tokyo 113-8510; Second Department of Pathology, National Defense Medical College, Saitama 359-8513 [H. T.]; Department of Gynecology, Kyoundo Hospital, Sasaki Institute, Tokyo 101-0062 [M. S.]; and Pathology Division, National Cancer Center Research Institute, Tokyo 104-0045 [S. H.], Japan

Inhibition of, or increased resistance to, apoptosis is a common property of cancer cells. This means that a constitutive activation of antiapoptotic molecules via genetic or epigenetic mechanisms, including gene amplification, may well be involved in carcinogenesis. Recently we reported that cIAP1, an inhibitor of apoptosis, is overexpressed through 11q22 amplification in cell lines derived from esophageal squamous cell carcinomas and is associated with resistance of esophageal squamous cell carcinomas to drug-induced apoptosis (I. Imoto et al. Cancer Res., 61: 6629–6634, 2001). Because amplification of 11q22 has been implicated in other malignancies also, including cervical squamous cell carcinomas (CSCCs), we attempted to correlate amplification and overexpression of cIAP1 with radiation sensitivity in CSCC-derived cell lines and primary CSCC tumors. In the nine cell lines we examined, two showed amplification and consistent overexpression of cIAP1, as well as significant resistance to radiation-induced cell death as compared with lines showing no cIAP1 amplification. Immunohistochemical analysis of 70 primary CSCCs from patients treated only with radiotherapy demonstrated that both overall survival and local recurrence-free survival was significantly poorer among patients with tumors showing high levels of nuclear cIAP1 staining than among patients whose tumors revealed little or no nuclear cIAP1. Multivariate analysis showed nuclear cIAP1 staining to be an independent predictive factor for local recurrence-free survival after radiotherapy among patients with CSCC. These findings demonstrate that cIAP1 may play an important role in the development/progression of this disease and that cIAP1 could be a novel predictive marker for resistance to radiotherapy in individual CSCC patients.

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