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
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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. / Volkmann, Juliane; Reuning, Ute; Rudelius, Martina; Häfner, Norman; Schuster, Tibor; Becker V Ros, Aaron; Weimer, Joerg; Hilpert, Felix; Kiechle, Marion; Dürst, Matthias; Arnold, Norbert; Schmalfeldt, Barbara; Meindl, Alfons; Ramser, Juliane.
in: INT J CANCER, Jahrgang 132, Nr. 12, 15.06.2013, S. 2820-32.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - 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
AU - Volkmann, Juliane
AU - Reuning, Ute
AU - Rudelius, Martina
AU - Häfner, Norman
AU - Schuster, Tibor
AU - Becker V Ros, Aaron
AU - Weimer, Joerg
AU - Hilpert, Felix
AU - Kiechle, Marion
AU - Dürst, Matthias
AU - Arnold, Norbert
AU - Schmalfeldt, Barbara
AU - Meindl, Alfons
AU - Ramser, Juliane
N1 - Copyright © 2012 UICC.
PY - 2013/6/15
Y1 - 2013/6/15
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Antineoplastic Agents
KW - Apoptosis
KW - Caspase 3
KW - Cell Line, Tumor
KW - Cisplatin
KW - Enzyme Activation
KW - Female
KW - Humans
KW - Middle Aged
KW - Neoplasm Staging
KW - Ovarian Neoplasms
KW - Prognosis
KW - RNA, Messenger
KW - TNF-Related Apoptosis-Inducing Ligand
KW - Tumor Markers, Biological
KW - alpha-Crystallin B Chain
U2 - 10.1002/ijc.27975
DO - 10.1002/ijc.27975
M3 - SCORING: Journal article
C2 - 23225306
VL - 132
SP - 2820
EP - 2832
JO - INT J CANCER
JF - INT J CANCER
SN - 0020-7136
IS - 12
ER -
