title: Six1 overexpression in ovarian carcinoma causes resistance to TRAIL-mediated apoptosis and is associated with poor survival.
abstract: Tumorigenesis can arise from inappropriate activation of developmental genes in mature tissues. Here, we show that the developmental regulator Six1 is overexpressed in ovarian carcinoma cell lines (OCC) compared with normal ovarian surface epithelium. As observed in other cancers, Six1 overexpression in OCC leads to increased A-type cyclin expression and increased proliferation. In addition, Six1 overexpression renders OCC resistant to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis, and Six1 knockdown in the TRAIL-resistant SKOV3 ovarian carcinoma line dramatically sensitizes the cells to TRAIL. Because inactivation of the TRAIL response has been linked to metastasis, and because antibodies and recombinant ligand that activate the TRAIL pathway are currently in clinical trials against ovarian carcinoma, we screened normal ovarian and carcinoma specimens for Six1 mRNA. Six1 was overexpressed in 50% of the early-stage (stage I) and 63% of the late-stage (stages II, III, and IV) ovarian carcinomas examined, with late-stage carcinomas expressing approximately 3-fold higher Six1 mRNA levels on average compared with early-stage tumors. Importantly, in patients with late-stage disease, high Six1 expression was associated with significantly shortened survival (P = 0.0015). These data suggest that Six1 may contribute to ovarian epithelial carcinogenesis by simultaneously increasing proliferation and decreasing TRAIL-mediated apoptosis and imply that Six1 may be an important determinant of TRAIL therapy response that should be considered in patient selection for TRAIL-related clinical trials.
authors.affiliation: Division of Basic Reproductive Sciences and Gynecologic Oncology in the Department of Obstetrics and Gynecology, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado, USA.
authors.forename: Kian
authors.initials: K
authors.lastname: Behbakht
authors.forename: Lubna
authors.initials: L
authors.lastname: Qamar
authors.forename: Carrie S
authors.initials: CS
authors.lastname: Aldridge
authors.forename: Ricardo D
authors.initials: RD
authors.lastname: Coletta
authors.forename: Susan A
authors.initials: SA
authors.lastname: Davidson
authors.forename: Andrew
authors.initials: A
authors.lastname: Thorburn
authors.forename: Heide L
authors.initials: HL
authors.lastname: Ford
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010053:Ovary / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014162:Transfection
chemical_list: D018398:Homeodomain Proteins; D012333:RNA, Messenger; C099236:SIX1 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand