X-chromosome-linked inhibitor of apoptosis as a key factor for chemoresistance in clear cell carcinoma of the ovary.
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.
Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
M
M
Miyamoto
Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
M
M
Takano
Department of Basic Pathology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
K
K
Iwaya
Department of Molecular Biology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
N
N
Shinomiya
Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
M
M
Kato
Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
T
T
Aoyama
Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
N
N
Sasaki
Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
T
T
Goto
Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
A
A
Suzuki
Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
J
J
Hitrata
Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
K
K
Furuya
D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000627:therapeutic use; D018572:Disease-Free Survival; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis / Q000235:genetics*; D051020:bcl-X Protein / Q000096:biosynthesis
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D014408:Biomarkers, Tumor; D034741:RNA, Small Interfering; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein; D019859:Proto-Oncogene Proteins c-met; D002945:Cisplatin