title: GATA4 protects granulosa cell tumors from TRAIL-induced apoptosis.
abstract: Disturbances in granulosa cell apoptosis have been implicated in the pathogenesis of human granulosa cell tumors (GCTs). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent cytokine that induces apoptosis in a variety of malignancies without toxic effects on benign cells. The aim of this study was to investigate the expression and functionality of the TRAIL receptors DR4 and DR5 in human GCTs. Additionally, we examined the role of GATA4, a transcription factor expressed in normal and malignant granulosa cells, in TRAIL-induced GCT apoptosis. For this purpose, a tissue microarray of 80 primary and 12 recurrent GCTs was subjected to immunohistochemistry for DR4 and DR5, and freshly isolated primary GCT cultures were utilized to evaluate the functional effects of TRAIL on GCT cells. To clarify the role of GATA4 in the regulation of TRAIL-induced apoptosis, a human GCT-derived cell line (KGN) was transduced with lentiviral vectors expressing small hairpin RNAs targeting GATA4 or transfected with adenovirus expressing either wild-type or dominant negative mutant GATA4. We found that receptors DR4 and DR5 are expressed in a vast majority of GCTs as well as in primary GCT cultures, and that TRAIL induces apoptosis in the primary GCT cultures. Moreover, we showed that overexpressing GATA4 protects GCTs from TRAIL-induced apoptosis in vitro, whereas disrupting GATA4 function induces apoptosis and potentiates the apoptotic effect of TRAIL administration. Our results demonstrate that the TRAIL pathway is functional in GCT cells, and suggest that transcription factor GATA4 may function as a survival factor in this ovarian malignancy.
authors.affiliation: Children's Hospital, University of Helsinki, PO Box 22 Stenbäckinkatu 11, 00014 Helsinki, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Kyrönlahti
authors.forename: Marjut
authors.initials: M
authors.lastname: Kauppinen
authors.forename: Essi
authors.initials: E
authors.lastname: Lind
authors.forename: Leila
authors.initials: L
authors.lastname: Unkila-Kallio
authors.forename: Ralf
authors.initials: R
authors.lastname: Butzow
authors.forename: Juha
authors.initials: J
authors.lastname: Klefström
authors.forename: David B
authors.initials: DB
authors.lastname: Wilson
authors.forename: Mikko
authors.initials: M
authors.lastname: Anttonen
authors.forename: Markku
authors.initials: M
authors.lastname: Heikinheimo
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D005260:Female; D050991:GATA4 Transcription Factor / Q000378:metabolism*; D006106:Granulosa Cell Tumor / Q000378:metabolism* / Q000473:pathology*; D006107:Granulosa Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D046888:Tissue Array Analysis
chemical_list: D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human