Phenotypic plasticity of the ovarian surface epithelium: TGF-beta 1 induction of epithelial to mesenchymal transition (EMT) in vitro.
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.
Zhu
Yihong
Y
Institute of Clinical Sciences, Department of Obstetrics and Gynaecology, Sahlgrenska Academy at Gothenburg University, SE-413 45 Gothenburg, Sweden.
Nilsson
Mikael
M
Sundfeldt
Karin
K
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
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