Document Detail


The transforming growth factor-beta (TGF-β) mediates acquisition of a mesenchymal stem cell-like phenotype in human liver cells.
MedLine Citation:
PMID:  20945437     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Transforming growth factor-beta (TGF-β) mediates several and sometime opposite effects in epithelial cells, inducing growth inhibition, and apoptosis but also promoting an epithelial to mesenchymal transition (EMT) process, which enhances cell migration and invasion. TGF-β plays relevant roles in different liver pathologies; however, very few is known about its specific signaling and cellular effects in human primary hepatocytes. Here we show that TGF-β inhibits proliferation and induces pro-apoptotic genes (such as BMF or BIM) in primary cultures of human fetal hepatocytes (HFH), but also up-regulates anti-apoptotic genes, such as BCL-XL and XIAP. Inhibition of the epidermal growth factor receptor (EGFR), using gefitinib, abrogates the increase in the expression of the anti-apoptotic genes and significantly enhances cell death. Simultaneously, TGF-β is able to induce an EMT process in HFH, coincident with Snail up-regulation and a decrease in E-cadherin levels, cells showing mesenchymal proteins and reorganization of the actin cytoskeleton in stress fibers. Interestingly, these cells show loss of expression of specific hepatic genes and increased expression of stem cell markers. Chronic treatment with TGF-β allows selection of a population of mesenchymal cells with a de-differentiated phenotype, reminiscent of progenitor-like cells. Process is reversible and the mesenchymal stem-like cells re-differentiate to hepatocytes under controlled experimental conditions. In summary, we show for the first time that human hepatocytes may respond to TGF-β inducing different signals, some of them might contribute to tumor suppression (growth inhibition and apoptosis), but others should mediate liver tumor progression and invasion (EMT and acquisition of a stem-like phenotype).
Authors:
Laia Caja; Esther Bertran; Jean Campbell; Nelson Fausto; Isabel Fabregat
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of cellular physiology     Volume:  226     ISSN:  1097-4652     ISO Abbreviation:  J. Cell. Physiol.     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-02-22     Completed Date:  2011-04-14     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  0050222     Medline TA:  J Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1214-23     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Wiley-Liss, Inc.
Affiliation:
Biological Clues of Invasive and Metastatic Phenotype Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain. lcaja@idibell.cat
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / genetics
Apoptosis Regulatory Proteins / genetics,  metabolism
Cadherins / metabolism
Carcinoma, Hepatocellular / metabolism,  pathology
Cell Proliferation
Cell Transdifferentiation* / drug effects,  genetics
Cells, Cultured
Gene Expression Regulation
Hepatocytes / drug effects,  metabolism*,  pathology
Humans
Liver / drug effects,  embryology,  metabolism*,  pathology
Liver Neoplasms / metabolism,  pathology
Mesenchymal Stromal Cells / drug effects,  metabolism*
Neoplasm Invasiveness
Phenotype
Protein Kinase Inhibitors / pharmacology
Quinazolines / pharmacology
Receptor, Epidermal Growth Factor / antagonists & inhibitors,  metabolism
Recombinant Proteins / metabolism
Signal Transduction* / drug effects,  genetics
Transcription Factors / metabolism
Transforming Growth Factor beta1 / metabolism*
Grant Support
ID/Acronym/Agency:
R01CA074131/CA/NCI NIH HHS; R01CA127228/CA/NCI NIH HHS; R37CA023226/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/CDH1 protein, human; 0/Cadherins; 0/Protein Kinase Inhibitors; 0/Quinazolines; 0/Recombinant Proteins; 0/TGFB1 protein, human; 0/Transcription Factors; 0/Transforming Growth Factor beta1; 0/snail family transcription factors; EC 2.7.10.1/EGFR protein, human; EC 2.7.10.1/Receptor, Epidermal Growth Factor; S65743JHBS/gefitinib

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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