X-chromosome-linked inhibitor of apoptosis as a key factor for chemoresistance in clear cell carcinoma of the ovary

Abstract

Background: X-chromosome-linked inhibitor of apoptosis (XIAP) is one of the anti-apoptotic proteins leading to chemoresistance in several cancers. The aim of this study is to evaluate the impact of XIAP expression upon ovarian clear cell carcinoma (CCC) that has a platinum-resistant phenotype.

Methods: Tissue microarrays made from 90 CCC patients were analysed for immunohistochemical expression levels of XIAP, c-Met, p-Akt and Bcl-XL. In addition, CCC cell lines were evaluated whether XIAP silencing could modulate sensitivity to platinum agent in vitro.

Results: High XIAP expression was observed in 30 (33%) of 90 CCC cases, and was associated with c-Met (<0.01) and Bcl-XL (<0.01) expression. Cases with high XIAP expression had lower response rate to primary platinum-based chemotherapy (10% vs 65%, P=0.02). In stages II-IV tumours, high XIAP expression was related with worse progression-free survival (PFS, P=0.02). Furthermore, high XIAP expression was identified as an independent worse prognostic factor for PFS and overall survival. Finally, downregulation of XIAP using XIAP-specific small interfering RNA increased sensitivity to cisplatin in human cancer cells derived from CCC.

Conclusions: X-chromosome-linked inhibitor of apoptosis expression was correlated with chemoresistance of primary chemotherapy, and identified as a prognostic marker for CCC. X-chromosome-linked inhibitor of apoptosis could be a candidate for new therapeutic target in CCC.

Figure 1

Progression-free survival (PFS) and overall survival (OS) curves of the patients with stages II–IV clear cell carcinoma of the ovary according to XIAP expression. (A) Progression-free survival curves of the patients. The patients with high expression of XIAP had significantly worse PFS (P=0.02). (B) Overall survival curves of the patients. Although high expression of XIAP was related with poor survival, significant difference was not observed in two groups (P=0.07).

Figure 2

Downregulation of XIAP by transfection with XIAP siRNA and sensitivity to cisplatin in vitro. (A) Clear cell carcinoma cell line, KK, was transfected with nonspecific siRNA (KK-C), XIAP-specific siRNA I (KK-I) and XIAP-specific siRNA II (KK-II). Expression ratio of XIAP protein compared with KK cells without transfection was as follows: 73.14±12.7% in KK-C, 20.6±3.94% in KK-I and 19.54±6.67% in KK-II, respectively. Phospho-Akt expression was decreased in KK-I and KK-II cells compared with KK-C: 62.9±11.0% in KK-I, 64.5±4.6% in KK-II. (B) After transfection, these cells were treated with for 24 h at a dose of 10 μM. Expression levels of cleaved caspase-3 and cleaved PARP increased in both KK-I and KK-II cells compared with KK or KK-C. (C) Apoptosis fractions induced by 24-h treatment of cisplatin in KK-C, KK-I and KK-II were shown. Ratio of apoptotic fraction was higher in KK-I and KK-II compared with that of KK-C at each concentration. The data represented the mean ± s.d. of at least four times. *P<0.01.