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High expression of crystallin αB represents an independent molecular marker for unfavourable ovarian cancer patient outcome and impairs TRAIL‐ and cisplatin‐induced apoptosis in human ovarian cancer cells
Author(s) -
Volkmann Juliane,
Reuning Ute,
Rudelius Martina,
Häfner Norman,
Schuster Tibor,
v. Rose Aaron Becker,
Weimer Joerg,
Hilpert Felix,
Kiechle Marion,
Dürst Matthias,
Arnold Norbert,
Schmalfeldt Barbara,
Meindl Alfons,
Ramser Juliane
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27975
Subject(s) - ovarian cancer , cisplatin , apoptosis , cancer , oncology , hazard ratio , cancer research , medicine , immunohistochemistry , biomarker , cancer cell , taxane , biology , chemotherapy , breast cancer , confidence interval , biochemistry
Dysregulated apoptotic pathways are regarded as major reasons for chemoresistance development as a particular challenge in ovarian cancer therapy. In search of molecular factors affecting human ovarian cancer cell apoptosis and, consequently, patient survival, we examined tumors of 103 platinum‐/taxane‐treated ovarian cancer patients by mRNA‐array hybridization, qPCR, and immunohistochemistry. We identified high expression of crystallin αB (CRYAB), a proposed negative regulator of tumor necrosis factor‐related apoptosis inducing ligand (TRAIL)‐mediated apoptosis. By Kaplan Meier analysis, this factor turned out to be significantly associated with poor patient outcome [overall survival (OS) p = 0.001, recurrence‐free survival (RFS) p = 0.003]. Elevated hazard ratios (HR) were estimated with regard to OS (HR = 2.11, 95% CI 1.10–4.06) and RFS (HR = 1.92, 95% CI 1.07–3.47) in multivariable analyses. These associations were confirmed in independent, publicly available mRNA data comprising 431 patients for OS ( p < 0.001) and 413 for RFS ( p < 0.001) . Our findings were validated by studying apoptotic events in cultured human ovarian cancer cells which were stably transfected to express elevated CRYAB levels. These data emphasized the crucial role of CRYAB in human ovarian cancer biology since TRAIL‐ as well as cisplatin‐induced apoptosis was significantly impaired as a function of enhanced CRYAB expression. Taken together, we identified CRYAB as an independent biomarker for unfavourable outcome of human ovarian cancer patients. Since TRAIL is currently tested as anti‐cancer drug and large proportions of the present patient cohort displayed low CRYAB levels in their tumors, CRYAB may enable the selection of patient subgroups benefiting most from TRAIL‐containing therapy.