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Molecular Cancer Research 1:68-78 (2002)
© 2002 American Association for Cancer Research

Signaling and Regulation

The Epithelial Mesenchymal Transition Confers Resistance to the Apoptotic Effects of Transforming Growth Factor ß in Fetal Rat Hepatocytes1

Francisco Valdés1, Alberto M. Álvarez2, Annamaria Locascio3, Sonia Vega3, Blanca Herrera1, Margarita Fernández1, Manuel Benito1, M. Angela Nieto3 and Isabel Fabregat1

1 Departamento de Bioquímica y Biología Molecular, Instituto de Bioquímica, Centro Mixto CSIC/UCM, Facultad de Farmacia, 2 Centro de Citometría de Flujo y Microscopía Confocal, Universidad Complutense de Madrid, Madrid, Spain; and
3 Instituto Cajal, CSIC, Madrid, Spain

Requests for reprints: Isabel Fabregat, Departamento de Bioquímica y Biología Molecular, Instituto de Bioquímica, Centro Mixto CSIC/UCM, Facultad de Farmacia, Universidad Complutense de Madrid, Ciudad Universitaria, 28040 Madrid, Spain. Phone: 34-91-3941627; Fax: 34-91-3941779. E-mail: isabelf{at}farm.ucm.es

Fetal rat hepatocytes treated with transforming growth factor ß (TGF-ß) die by apoptosis. However, a subpopulation of them survives and undergoes an epithelial mesenchymal transition (EMT). This transition also occurs upon incubation with fetal bovine serum. We have isolated the subpopulations that undergo EMT (TGF-ß-treated-fetal hepatocytes: TßT-FH; serum-treated-fetal hepatocytes: ST-FH) and show that they present high levels of vimentin and Snail expression and lack cytokeratin 18 and E-cadherin. Both TßT-FH and ST-FH cells require mitogens to grow and maintain the response to TGF-ß in terms of growth inhibition. However, they lack differentiation markers such as the liver-enriched transcription factors hepatocyte nuclear factor 4 (HNF-4) or HNF-1{alpha} and express the progenitor marker OV-6. Interestingly, the EMT process confers them resistance to the apoptotic effect of TGF-ß, with cells showing higher levels of active AKT and Bcl-xL than fetal hepatocytes. In summary, these cells are refractory to the apoptotic effects of TGF-ß, showing characteristics of liver progenitors and of some hepatocellular carcinoma cells.




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Copyright © 2002 by the American Association for Cancer Research.