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Fas and Its Ligand, Caspases, and Bcl-2 Expression in Gonadotropin-Releasing Hormone Agonist-Treated Uterine Leiomyoma

Department of Obstetrics and Gynecology (S.-C.H., K.-F.H., Y.-M.C., C.-Y.C.), Institute of Clinical Medicine (S.-C.H., M.-J.T., K.-F.H., C.-Y.C.), and Department of Physiology (M.-J.T.), College of Medicine, National Cheng Kung University, Tainan 704, Taiwan

Address all correspondence and requests for reprints to: Cheng-Yang Chou, M.D., Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 704, Taiwan. E-mail: chougyn{at}mail.ncku.edu.tw.

Abstract

GnRH agonist (GnRH-a) therapy is known to shrink uterine leiomyoma, although the molecular mechanisms responsible for this effect remain poorly understood. Conflicting results exist as to whether GnRH-a treatment increases apoptosis in leiomyoma cells. The aim of this study is to investigate the effects of GnRH-a on uterine leiomyomas by profiling the expression levels of apoptosis-related molecules such as Fas/Fas ligand (FasL), caspases 3, 6, 7, 8, 9, and 10, and Bcl-2 from specimens of 20 patients receiving Leuplin Depot (LA), a long-acting GnRH-a, of 3 doses before myomectomy, as well as 24 controls. We found that uterine leiomyomas had up-regulated expressions of FasL and caspase 3 as compared with their homologous normal myometrium control. Both leiomyomas and myometria from LA-treated patients, however, presented a significant decrease in the expressions of FasL and caspase 3 as compared with those from LA-naive control patients. In addition, it was at the posttranscription level that the tumorigenesis of leiomyoma modulated the expressions of FasL and caspase 3 higher, whereas LA suppressed them at gene transcription. Unlike the case of FasL and caspase 3 mentioned above, no significant difference was found between leiomyomas and homologous myometria in the expressions of Fas and caspases 6, 7, 8, 9, and 10. The LA effect made drug-treated leiomyomas produce less Fas and caspases 7, 9, and 10 as compared with nontreated leiomyomas. Immunohistochemical analysis showed that both Fas and FasL were localized predominantly in cytosol. Moreover, leiomyomas had an up-regulated Bcl-2 level, which remained high even in the LA-treated cells. Our findings provide molecular evidence to support our previous observations that GnRH-a therapy fails to increase apoptosis in uterine leiomyomas.

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