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

@article{citeulike:5816042, abstract = {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[beta], 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. 10.1152/ajpcell.00478.2005}, author = {Ahmed, Nuzhat and Maines-Bandiera, Sarah and Quinn, Michael A. and Unger, Waldemar G. and Dedhar, Shoukat and Auersperg, Nelly}, citeulike-article-id = {5816042}, citeulike-linkout-0 = {http://dx.doi.org/10.1152/ajpcell.00478.2005}, citeulike-linkout-1 = {http://ajpcell.physiology.org/content/290/6/C1532.abstract}, citeulike-linkout-2 = {http://ajpcell.physiology.org/content/290/6/C1532.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/16394028}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=16394028}, day = {1}, doi = {10.1152/ajpcell.00478.2005}, issn = {0363-6143}, journal = {Am J Physiol Cell Physiol}, keywords = {cancer, egf, emt, erk, mek, ovary, rac, ras}, month = {June}, number = {6}, pages = {C1532--1542}, posted-at = {2009-09-21 20:46:53}, priority = {2}, title = {Molecular pathways regulating EGF-induced epithelio-mesenchymal transition in human ovarian surface epithelium}, url = {http://dx.doi.org/10.1152/ajpcell.00478.2005}, volume = {290}, year = {2006} }

TY - JOUR ID - citeulike:5816042 L3 - citeulike-article-id:5816042 N2 - 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[beta], 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. 10.1152/ajpcell.00478.2005 IS - 6 JF - Am J Physiol Cell Physiol SN - 0363-6143 EP - 1542 TI - Molecular pathways regulating EGF-induced epithelio-mesenchymal transition in human ovarian surface epithelium VL - 290 SP - C1532 KW - cancer KW - egf KW - emt KW - erk KW - mek KW - ovary KW - rac KW - ras AU - Ahmed, Nuzhat AU - Maines-Bandiera, Sarah AU - Quinn, Michael AU - Unger, Waldemar AU - Dedhar, Shoukat AU - Auersperg, Nelly PY - 2006/06/01/ UR - http://dx.doi.org/10.1152/ajpcell.00478.2005 ER -