PMID- 25098666
OWN - NLM
STAT- MEDLINE
DCOM- 20150211
LR  - 20151119
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 60
IP  - 6
DP  - 2014 Dec
TI  - Inflammatory cytokines promote the retrodifferentiation of tumor-derived 
      hepatocyte-like cells to progenitor cells.
PG  - 2077-90
LID - 10.1002/hep.27353 [doi]
AB  - Human hepatocellular carcinoma (HCC) heterogeneity promotes recurrence and 
      resistance to therapies. Recent studies have reported that HCC may be derived not 
      only from adult hepatocytes and hepatoblasts but also hepatic stem/progenitors. 
      In this context, HepaRG cells may represent a suitable cellular model to study 
      stem/progenitor cancer cells and the retrodifferentiation of tumor-derived 
      hepatocyte-like cells. Indeed, they differentiate into hepatocyte- and 
      biliary-like cells. Moreover, tumor-derived HepaRG hepatocyte-like cells 
      (HepaRG-tdHep) differentiate into both hepatocyte- and biliary-like cells through 
      a hepatic progenitor. In this study we report the mechanisms and molecular 
      effectors involved in the retrodifferentiation of HepaRG-tdHep into bipotent 
      progenitors. Gene expression profiling was used to identify genomic changes 
      during the retrodifferentiation of HepaRG-tdHep into progenitors. We demonstrated 
      that gene expression signatures related to a poor-prognosis HCC subclass, 
      proliferative progenitors, or embryonic stem cells were significantly enriched in 
      HepaRG progenitors derived from HepaRG-tdHep. HepaRG-tdHep retrodifferentiation 
      is mediated by crosstalk between transforming growth factor beta 1 (TGFbeta1) and 
      inflammatory cytokine pathways (e.g., tumor necrosis factor alpha [TNFalpha] and 
      interleukin 6 [IL6]). Signatures related to TNFalpha, IL6, and TGFbeta activation 
      pathways are induced within the first hour of retrodifferentiation. Moreover, 
      specific activation or inhibition of these signaling pathways allowed us to 
      determine that TNFalpha and IL6 contribute to the loss of hepatic-specific marker 
      expression and that TGFbeta1 induces an epithelial-to-mesenchymal transition of 
      HepaRG-tdHep. Interestingly, the retrodifferentiation process is blocked by the 
      histone deacetylase inhibitor trichostatin A, opening new therapeutic 
      opportunities. CONCLUSION: Cancer progenitor cells (or metastasis progenitors) 
      may derive from tumor-derived hepatocyte-like cells in an inflammatory 
      environment that is frequently associated with HCC.
CI  - (c) 2014 by the American Association for the Study of Liver Diseases.
FAU - Dubois-Pot-Schneider, Helene
AU  - Dubois-Pot-Schneider H
AD  - Inserm, UMR991, Liver Metabolisms and Cancer, F-35033, Rennes, France; Universite 
      de Rennes 1, F-35043, Rennes, France.
FAU - Fekir, Karim
AU  - Fekir K
FAU - Coulouarn, Cedric
AU  - Coulouarn C
FAU - Glaise, Denise
AU  - Glaise D
FAU - Aninat, Caroline
AU  - Aninat C
FAU - Jarnouen, Kathleen
AU  - Jarnouen K
FAU - Le Guevel, Remy
AU  - Le Guevel R
FAU - Kubo, Takashi
AU  - Kubo T
FAU - Ishida, Seiichi
AU  - Ishida S
FAU - Morel, Fabrice
AU  - Morel F
FAU - Corlu, Anne
AU  - Corlu A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141029
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Biomarkers)
RN  - 0 (Hydroxamic Acids)
RN  - 0 (Interleukin-6)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 3X2S926L3Z (trichostatin A)
SB  - IM
MH  - Biomarkers/metabolism
MH  - *Cell Dedifferentiation
MH  - Cell Line
MH  - Epithelial-Mesenchymal Transition
MH  - Hepatocytes/*physiology
MH  - Humans
MH  - Hydroxamic Acids
MH  - Interleukin-6/*metabolism
MH  - Phenotype
MH  - Receptor Cross-Talk
MH  - Signal Transduction
MH  - Transforming Growth Factor beta/*metabolism
MH  - Tumor Necrosis Factor-alpha/*metabolism
EDAT- 2014/08/08 06:00
MHDA- 2015/02/12 06:00
CRDT- 2014/08/08 06:00
PHST- 2014/01/20 00:00 [received]
PHST- 2014/08/01 00:00 [accepted]
PHST- 2014/08/08 06:00 [entrez]
PHST- 2014/08/08 06:00 [pubmed]
PHST- 2015/02/12 06:00 [medline]
AID - 10.1002/hep.27353 [doi]
PST - ppublish
SO  - Hepatology. 2014 Dec;60(6):2077-90. doi: 10.1002/hep.27353. Epub 2014 Oct 29.