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This Article Full Text Full Text (PDF) All Versions of this Article: 290/6/C1532    most recent 00478.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (23) Citing Articles via Google Scholar Google Scholar Articles by Ahmed, N. Articles by Auersperg, N. Search for Related Content PubMed PubMed Citation Articles by Ahmed, N. Articles by Auersperg, N.

GROWTH, DIFFERENTIATION, AND APOPTOSIS

Molecular pathways regulating EGF-induced epithelio-mesenchymal transition in human ovarian surface epithelium

¹Gynaecological Cancer Research Centre, Royal Women's Hospital, Carlton, and Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne; ²Translational Proteomics, Baker Heart Research Institute, Melbourne, Victoria, Australia; ³Department of Obstetrics and Gynaecology and ⁴British Columbia Cancer Agency, The Prostate Centre at Vancouver Hospital, and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada

Submitted 26 September 2005 ; accepted in final form 17 November 2005

The ovarian surface epithelium (OSE) is the precursor of common epithelial ovarian carcinomas. In the present study, we examined the molecular mechanisms and possible physiological basis for the propensity of OSE cells to undergo epithelio-mesenchymal transition (EMT) in response to environmental influences. We hypothesized that EMT may be a homeostatic mechanism that permits displaced OSE to assume a stromal phenotype within the ovarian cortex. We report that EGF in conjunction with hydrocortisone is the EMT-inducing factor of OSE as shown by changes to a fibroblast-like morphology and growth pattern. EGF increased cell motility, enhanced the activities of secreted pro-matrix metalloproteinase (MMP)-2 and -9, and enhanced expression and activation of Erk and integrin-linked kinase (ILK). Increased ILK expression correlated with the activation of PKB/Akt, the phosphorylation of GSK-3, and the increased expression of cyclin E and cdk2 kinase. EGF withdrawal resulted in a more epithelial morphology and reversal of the EGF-induced activation of signaling pathways and pro-MMP activity. In contrast, treatment of EGF-treated cells with specific inhibitors of phosphatidylinositol 3-kinase, Mek, or ILK inhibited the inhibitor-specific pathways. The inhibitors caused suppression of EGF-induced migration and pro-MMP-2/-9 activities but did not lead to any change in EGF-induced mesenchymal morphology. ILK small interfering RNA inhibited Akt phosphorylation and reduced pro-MMP-2/-9 activities but had no effect on Erk activation or cell morphology. These results indicate that the EGF-induced morphological and functional changes in OSE cells are controlled by distinct signaling mechanisms working in concert. EMT of OSE cells displaced by ovulation likely permits their survival and integration with a fibroblast-like identity within the stroma. Failure to do so may lead to the formation of epithelium-derived inclusion cysts, which are known preferential sites of malignant transformation.

epidermal growth factor; migration; invasion

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