Little is known about the molecules that contribute to tumor growth in epithelial ovarian cancer (EOC) that remain the most lethal gynecological neoplasm. Glucocorticoid-Induced Leucine Zipper (GILZ), a leucine zipper protein of 17 kDa, is frequently detected in epithelial tissues with a hormonal background. We detected GILZ in EOC1 and we further demonstrated that this factor which expression is enhanced by estradiol (E2), activates tumor cell proliferation and up-regulates CXCR4, a chemokine receptor highly involved in tumor expansion. GILZ was detected by immunohistochemistry in tumors from 50 patients surgically treated for diagnosis of EOC at Antoine Béclère hospital from 1998 to 2007. Its expression scored from 1 to 7 was positively correlated to the proliferation marker Ki-67 (P<0.00001). It was also higher in tumors containing high amount of phosphorylated protein kinase B (p-AKT) (P<0.01). Cell proliferation increased in BG1 cells overexpressing GILZ by stable transfection of a GILZ-encoding vector whereas it decreased after silencing GILZ by the use of small interfering RNA. Modulation of GILZ expression changed the level of p21, cyclin D1 and phospho-retinoblastoma, three proteins that regulate cell cycle and are AKT targeted. Further GILZ increased phospho-AKT cellular content and AKT kinase activity. In mice xenografted with BG1 cells, tumor growth was faster in females. BG-1 cells treated with 10−9 M estradiol had a higher cellular content of GILZ. In parallel growth rate was faster and the expression of CXCR4 was higher, a chemokine which expression was also enhanced by GILZ as revealed by DNA microarray analysis of BG1 cells overexpressing GILZ. In conclusion, GILZ, a protein produced by ovarian cancer cells and which controls their proliferation and CXCR4 expression, is up regulated in estradiol-treated cells like proliferation and CXCR4. This reveals GILZ as a key molecule for estradiol action in EOC.
30 Apr - 04 May 2011
European Society of Endocrinology