title: 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.
abstract: 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.
authors.affiliation: Clinic of Gynecology and Obstetrics, Klinikum rechts der Isar, Technische Universitaet Muenchen, Munich, Germany. juliane.ramser@lrz.tum.de
authors.forename: Juliane
authors.initials: J
authors.lastname: Volkmann
authors.forename: Ute
authors.initials: U
authors.lastname: Reuning
authors.forename: Martina
authors.initials: M
authors.lastname: Rudelius
authors.forename: Norman
authors.initials: N
authors.lastname: Häfner
authors.forename: Tibor
authors.initials: T
authors.lastname: Schuster
authors.forename: Aaron
authors.initials: A
authors.lastname: Becker V Ros
authors.forename: Joerg
authors.initials: J
authors.lastname: Weimer
authors.forename: Felix
authors.initials: F
authors.lastname: Hilpert
authors.forename: Marion
authors.initials: M
authors.lastname: Kiechle
authors.forename: Matthias
authors.initials: M
authors.lastname: Dürst
authors.forename: Norbert
authors.initials: N
authors.lastname: Arnold
authors.forename: Barbara
authors.initials: B
authors.lastname: Schmalfeldt
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.forename: Juliane
authors.initials: J
authors.lastname: Ramser
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D038203:alpha-Crystallin B Chain / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; D038203:alpha-Crystallin B Chain; D053148:Caspase 3; D002945:Cisplatin