title: Differential expression of activin/inhibin subunit and activin receptor mRNAs in normal and neoplastic ovarian surface epithelium (OSE).
abstract: Ovarian surface epithelium (OSE) is the tissue of origin for the majority of ovarian cancers. The mechanism underlying the neoplastic transformation of OSE to ovarian cancer is poorly understood. Activin, a member of the transforming growth factor-beta superfamily, has been shown to increase cell proliferation in ovarian cancer cells. The present study was carried out to investigate the expression and regulation of activin/inhibin subunits and activin receptors in normal and neoplastic OSE. Using reverse transcriptase-polymerase chain reaction and Southern blot analysis, the mRNA levels of alpha, betaA and betaB subunits and activin receptor type IIA and IIB were analyzed in normal OSE and the ovarian cancer cell line, OVCAR-3 cells. The alpha and betaA subunits were highly expressed in normal OSE when compared to OVCAR-3 cells. By contrast, betaB subunit was highly expressed in OVCAR-3 cells, when compared to normal OSE cells. Interestingly, activin receptor IIB mRNA levels were significantly higher in OVCAR-3 when compared to normal OSE cells, whereas activin receptor IIA mRNA levels were the same in both cell types. To characterize the growth modulatory role of activin during neoplastic progression, normal OSE and OVCAR-3 cells were treated with recombinant human activin A (rh-activin A). At concentrations of 1,10 and 100 ng/ml, rh-activin A stimulated the growth of OVCAR-3 cells, but not of normal OSE. Treatment with follistatin, binding protein of activin, attenuates the stimulatory effect of activin. To determine whether the growth stimulatory action of activin in the neoplastic OSE is mediated via an autocrine regulatory mechanism, OVCAR-3 cells were treated with rh-activin A in a dose- and time-dependent manner and the expression levels of activin/inhibin subunits and activin receptors were investigated. Treatments with activin increased the alpha and betaA subunit mRNA levels in a dose- and time-dependent manner. However, no difference was observed in levels of betaB subunit, or in activin receptor type IIA and IIB mRNAs following activin treatments in OVCAR-3 cells. Taken together, these results suggest that different levels of activin/inhibin and activin receptor isoforms are expressed in normal and neoplastic OSE cells. In addition, the altered expression of the activin/inhibin subunits, as well as the cell proliferative effect of activin observed in OVCAR-3 but not in normal OSE cells, indicate that activin may act as an autocrine regulator of neoplastic OSE progression.
authors: Department of Obstetrics and Gynaecology, BC Women's Hospital, University of British Columbia, 2H-30, 4490 Oak Street, Vancouver, British Columbia, V6H 3V5, Canada.
authors: K C
authors: KC
authors: Choi
authors: S K
authors: SK
authors: Kang
authors: P S
authors: PS
authors: Nathwani
authors: K W
authors: KW
authors: Cheng
authors: N
authors: N
authors: Auersperg
authors: P C
authors: PC
authors: Leung
mesh_terms: D029404:Activin Receptors; D028341:Activins; D019898:Autocrine Communication; D002455:Cell Division / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006133:Growth Substances / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007265:Inhibins / Q000187:drug effects / Q000378:metabolism* / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000473:pathology*; D021122:Protein Subunits; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D006133:Growth Substances; D009363:Neoplasm Proteins; D021122:Protein Subunits; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D028341:Activins; D007265:Inhibins; D029404:Activin Receptors