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Carcinogenesis Advance Access published online on February 1, 2007
Carcinogenesis, doi:10.1093/carcin/bgm015
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

BMP4 induces EMT and Rho GTPase activation in human ovarian cancer cells

Brigitte L. Thériault, Trevor G. Shepherd, Michelle L. Mujoomdar and Mark W. Nachtigal

Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada B3H 1X5

Address correspondence to: Mark W. Nachtigal, Department of Pharmacology, Faculty of Medicine, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, NS, Canada B3H 1X5, Tel. (902) 494-6348; Fax. (902) 494-1388; Email: mark.nachtigal{at}dal.ca

We previously identified an autocrine BMP4 signalling pathway in primary human normal ovarian surface epithelial and epithelial ovarian cancer cells. Herein we show that treatment of ovarian cancer 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 ovarian cancer cell motility and adherence. In response to exogenous BMP4, the epithelial-mesenchymal transition markers Snail and Slug mRNA and protein were upregulated, E-cadherin mRNA and protein was downregulated, 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 ovarian cancer cells treated with BMP4, strongly suggesting that the changes in morphology, adhesion, motility and invasion are likely mediated through the activation of these molecules. Strikingly, treatment of normal ovarian surface epithelial cells with BMP4 or Noggin failed to alter cell motility, providing evidence that ovarian surface epithelial and ovarian cancer 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 ovarian cancer behaviour.

Key Words: bone morphogenetic protein • Noggin • ovarian surface epithelium • ovarian cancer • epithelial-mesenchymal transition • Rho GTPase


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