Carcinogenesis Advance Access originally published online on February 1, 2007
Carcinogenesis 2007 28(6):1153-1162; doi:10.1093/carcin/bgm015
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BMP4 induces EMT and Rho GTPase activation in human ovarian cancer cells
Department of Pharmacology, Faculty of Medicine, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5
* To whom correspondence should be addressed. Tel: +902 494 6348; Fax: +902 494 1388; Email: mark.nachtigal{at}dal.ca
We identified previously an autocrine bone morphogenetic protein-4 (BMP4) signalling pathway in primary human normal ovarian surface epithelial (OSE) and epithelial ovarian cancer (OvCa) cells. Herein we show that treatment of OvCa cells with BMP4 produced morphological alterations and increased cellular adhesion, motility and invasion. The BMP4 inhibitor noggin blocked the BMP4-induced phenotype, and decreased autocrine BMP4-mediated OvCa cell motility and adherence. In response to exogenous BMP4, the epithelial–mesenchymal transition (EMT) markers Snail and Slug mRNA and protein were up-regulated, E-cadherin mRNA and protein were down-regulated and the network of alpha smooth muscle actin changed to resemble a mesenchymal cell. We also observed changes in the level of activated Rho GTPases in OvCa cells treated with BMP4, strongly suggesting that the changes in morphology, adhesion, motility and invasion are probably mediated through the activation of these molecules. Strikingly, treatment of normal OSE cells with BMP4 or noggin failed to alter cell motility, providing evidence that OSE and OvCa cells possess a distinct capability to respond to BMP4. Overall, our studies suggest a link between autocrine BMP signalling mediated through the Rho GTPase family and Snail- and Slug-induced EMT that may collectively contribute to aggressive OvCa behaviour.
Abbreviations: BMP, bone morphogenetic protein; BSA, bovine serum albumin; EMT, epithelial–mesenchymal transition; FAP, focal adhesion protein; FBS, fetal bovine serum; LIMK1, LIM Kinase 1; NT, non-transduced; OSE, ovarian surface epithelial; OvCa, ovarian cancer; PBS, phosphate-buffered saline; QPCR, quantitative polymerase chain reaction; RT, room temperature
Received October 2, 2006; revised January 12, 2007; accepted January 15, 2007.
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