The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor Beta in fetal rat hepatocytes.
Fetal rat hepatocytes treated with transforming growth factor beta (TGF-beta) 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-beta-treated-fetal hepatocytes: TbetaT-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 TbetaT-FH and ST-FH cells require mitogens to grow and maintain the response to TGF-beta 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-1alpha and express the progenitor marker OV-6. Interestingly, the EMT process confers them resistance to the apoptotic effect of TGF-beta, with cells showing higher levels of active AKT and Bcl-x(L) than fetal hepatocytes. In summary, these cells are refractory to the apoptotic effects of TGF-beta, showing characteristics of liver progenitors and of some hepatocellular carcinoma cells.
Valdés
Francisco
F
Departamento de Bioquímica y Biología Molecular, Instituto de Bioquímica, Centro Mixto CSIC/UCM, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
Alvarez
Alberto M
AM
Locascio
Annamaria
A
Vega
Sonia
S
Herrera
Blanca
B
Fernández
Margarita
M
Benito
Manuel
M
Nieto
M Angela
MA
Fabregat
Isabel
I
D000818:Animals; D000943:Antigens, Differentiation / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008648:Mesoderm / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000032:analysis; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014746:Vimentin / Q000187:drug effects; D051020:bcl-X Protein
D000943:Antigens, Differentiation; C494811:BCL2L1 protein, human; C494813:Bcl2l1 protein, rat; D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014746:Vimentin; D051020:bcl-X Protein; C115011:oval cell marker OV-6; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt