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Expression of Betaglycan, an Inhibin Coreceptor, in Normal Human Ovaries and Ovarian Sex Cord-Stromal Tumors and Its Regulation in Cultured Human Granulosa-Luteal Cells

Department of Pathology (J.L., R.B., R.V.), Haartman Institute, University of Helsinki, FIN-00014 Helsinki, Finland; Departments of Pediatrics (T.K., T.V., R.V.) and Pathology and Forensic Medicine (V.-M.K.), Kuopio University Hospital and University of Kuopio, FIN-70211 Kuopio, Finland; Department of Pathology, Center for Laboratory Medicine, Tampere University Hospital (V.-M.K.), FIN-33521 Tampere, Finland; and Department of Obstetrics and Gynecology, Helsinki University Central Hospital (R.B., C.H.-G.), FIN-00290 Helsinki, Finland

Address all correspondence and requests for reprints to: Dr. Jianqi Liu, Department of Pathology, P.O. Box 21 Haartman Institute, University of Helsinki, FIN-00014 Helsinki, Finland. E-mail: jiangi.liu{at}helsinki.fi.

Activins and inhibins are often antagonistic in the regulation of ovarian function. TGFß type III receptor, betaglycan, has been identified as a coreceptor to enhance the binding of inhibins to activin type II receptor and thus to prevent the binding of activins to their receptor. In this study we characterized the expression and regulation pattern of betaglycan gene in normal ovaries and sex cord-stromal tumors and in cultured human granulosa-luteal cells from women undergoing in vitro fertilization. Expression of betaglycan mRNA was detected by RT-PCR or Northern blotting in normal ovarian granulosa, thecal, and stroma cells as well as in granulosa-luteal cells. Immunohistochemical analysis revealed positive staining for betaglycan in antral and preovulatory follicular granulosa and thecal cells and in corpora lutea of normal ovaries. Furthermore, betaglycan expression was detected in the vast majority of granulosa cell tumors, thecomas, and fibromas, with weaker staining in granulosa cell tumors compared with fibrothecomas. In cultured granulosa-luteal cells, FSH and LH treatment increased dose-dependently the accumulation of betaglycan mRNA, as did the protein kinase A activator dibutyryl cAMP and the protein kinase C inhibitor staurosporine. In contrast, the protein kinase C activator 12-O-tetradecanoyl phorbol 13-acetate had no significant effect on betaglycan mRNA levels. Treatment with prostaglandin E₂ and with its receptor EP2 subtype agonist butaprost increased betaglycan mRNA accumulation and progesterone secretion dose- and time-dependently. In summary, betaglycan gene is expressed in normal human ovarian steroidogenic cells and sex cord-stromal ovarian tumors. The accumulation of its mRNA in cultured granulosa-luteal cells is up-regulated by gonadotropins and prostaglandin E₂, probably via the protein kinase A pathway. The specific expression and regulation pattern of betaglycan gene may be related to the functional antagonism of inhibins to activin signal transduction in human ovaries.

This work was supported by the Jalmari and Rauha Ahokas Foundation, the Academy of Finland, the Sigrid Juselius Foundation, and Kuopio University Hospital.

Abbreviations: ActRII, Activin receptor type II; BMP, bone morphogenetic protein; (Bu)₂cAMP, dibutyryl cAMP; EP2, prostaglandin E receptor subtype 2; FLRG, follistatin-related gene; IVF, in vitro fertilization; PG, prostaglandin; rh, recombinant human; TPA, 12-O-tetradecanoyl phorbol 13-acetate.

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