PMID- 20041408
OWN - NLM
STAT- MEDLINE
DCOM- 20100222
LR  - 20130520
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 51
IP  - 2
DP  - 2010 Feb
TI  - Loss of hepatocyte nuclear factor 1alpha function in human hepatocellular 
      adenomas leads to aberrant activation of signaling pathways involved in 
      tumorigenesis.
PG  - 557-66
LID - 10.1002/hep.23362 [doi]
AB  - Hepatocellular adenomas (HCAs) are benign liver tumors that usually develop in 
      women who are taking oral contraceptives. Among these tumors, biallelic 
      inactivating mutations of the hepatocyte nuclear factor 1alpha (HNF1A) 
      transcription factor have been frequently identified and in rare cases of 
      hepatocellular carcinomas developed in noncirrhotic liver. Because HNF1A meets 
      the genetic criteria of a tumor suppressor gene, we aimed to elucidate the 
      tumorigenic mechanisms related to HNF1alpha inactivation in hepatocytes. We 
      searched for signaling pathways aberrantly activated in human HNF1A-mutated HCA 
      (H-HCA) using a genome-wide transcriptome analysis comparing five H-HCA with four 
      normal livers. We validated the main pathways by quantitative reverse 
      transcription polymerase chain reaction (RT-PCR) and western blotting in a large 
      series of samples. Then, we assessed the role of HNF1alpha in the observed 
      deregulations in hepatocellular cell models (HepG2 and Hep3B) by silencing its 
      endogenous expression using small interfering RNA. Along with the previously 
      described induction of glycolysis and lipogenesis, H-HCA also displayed 
      overexpression of several genes encoding growth factor receptors, components of 
      the translation machinery, cell cycle, and angiogenesis regulators, with, in 
      particular, activation of the mammalian target of rapamycin (mTOR) pathway. 
      Moreover, estradiol detoxification activities were shut down, suggesting a 
      hypersensitivity of H-HCA to estrogenic stimulation. In the cell model, 
      inhibition of HNF1alpha recapitulated most of these identified transcriptional 
      deregulations, demonstrating that they were related to HNF1alpha inhibition. 
      CONCLUSION: H-HCA showed a combination of alterations related to HNF1alpha 
      inactivation that may cooperate to promote tumor development. Interestingly, mTOR 
      appears as a potential new attractive therapeutic target for treatment of this 
      group of HCAs.
FAU - Pelletier, Laura
AU  - Pelletier L
AD  - Institut National de la Sante et de la Recherche Medicale, U674, Genomique 
      fonctionnelle des tumeurs solides, Paris, France.
FAU - Rebouissou, Sandra
AU  - Rebouissou S
FAU - Paris, Alain
AU  - Paris A
FAU - Rathahao-Paris, Estelle
AU  - Rathahao-Paris E
FAU - Perdu, Elisabeth
AU  - Perdu E
FAU - Bioulac-Sage, Paulette
AU  - Bioulac-Sage P
FAU - Imbeaud, Sandrine
AU  - Imbeaud S
FAU - Zucman-Rossi, Jessica
AU  - Zucman-Rossi J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Hepatocyte Nuclear Factor 1-alpha)
SB  - IM
MH  - Adenoma, Liver Cell/*etiology/genetics
MH  - Cell Line, Tumor
MH  - Gene Expression Regulation, Neoplastic
MH  - Hepatocyte Nuclear Factor 1-alpha/genetics/*physiology
MH  - Humans
MH  - Liver Neoplasms/*etiology/genetics
MH  - *Signal Transduction
MH  - Tumor Cells, Cultured
EDAT- 2009/12/31 06:00
MHDA- 2010/02/23 06:00
CRDT- 2009/12/31 06:00
PHST- 2009/12/31 06:00 [entrez]
PHST- 2009/12/31 06:00 [pubmed]
PHST- 2010/02/23 06:00 [medline]
AID - 10.1002/hep.23362 [doi]
PST - ppublish
SO  - Hepatology. 2010 Feb;51(2):557-66. doi: 10.1002/hep.23362.