title: Phenotypic plasticity of the ovarian surface epithelium: TGF-beta 1 induction of epithelial to mesenchymal transition (EMT) in vitro.
abstract: Ovarian surface epithelium (OSE) is the most conceivable cell origin of epithelial ovarian carcinomas. Unlike many other epithelial tumors, the precancerous lesion acquires expression of epithelial markers, e.g. E-cadherin and claudins, suggesting that OSE cells undergo mesenchymal to epithelial transition (MET) during transformation. Recent findings indicate that TGF-β1, a prototypic stimulus of epithelial to mesenchymal transition (EMT), i.e. reverse to MET, is produced at significant amounts in the intact ovary. In the present study, we therefore investigated whether TGF-β1 changes the OSE phenotype accordingly, focusing on epithelial junction proteins and transcriptional EMT regulators quantified by real-time RT-PCR and Western blotting in cultured normal human OSE. Early OSE passages were found to paradoxically express de novo E-cadherin and also establish tight junctions exhibiting claudin-1 (but not claudin-3 and -4) and occludin. Stimulation with TGF-β1 (100 ng/ml) for 3-5 d down-regulated all these epithelial markers including Crumbs3 and also prevented the formation of an epithelial barrier This was accompanied by sustained expression of Snail and N-cadherin and transient expression of Slug, whereas Zeb1 (zinc finger E-box binding homeobox 1) and Twist mRNA levels were not significantly changed. In conclusion, TGF-β1 enforces the mesenchymal phenotype of OSE cells in vitro by an EMT-like process, leading to an altered molecular composition of the epithelial junction complex that partly coincides with the expression pattern of the native OSE. This suggests a potential role of TGF-β1-induced EMT in OSE under physiological conditions and possibly also in epithelial ovarian tumorigenesis.
authors.affiliation: Institute of Clinical Sciences, Department of Obstetrics and Gynaecology, Sahlgrenska Academy at Gothenburg University, SE-413 45 Gothenburg, Sweden.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Zhu
authors.forename: Mikael
authors.initials: M
authors.lastname: Nilsson
authors.forename: Karin
authors.initials: K
authors.lastname: Sundfeldt
mesh_terms: D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D062445:Claudin-1; D015536:Down-Regulation; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D062793:Occludin; D010053:Ovary / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C568108:CLDN1 protein, human; C472002:CRB3 protein, human; D015820:Cadherins; D062445:Claudin-1; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D053773:Transforming Growth Factor beta1