PMID- 23857252
OWN - NLM
STAT- MEDLINE
DCOM- 20140303
LR  - 20140731
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 59
IP  - 1
DP  - 2014 Jan
TI  - MicroRNA/gene profiling unveils early molecular changes and nuclear factor 
      erythroid related factor 2 (NRF2) activation in a rat model recapitulating human 
      hepatocellular carcinoma (HCC).
PG  - 228-41
LID - 10.1002/hep.26616 [doi]
AB  - Studies on gene and/or microRNA (miRNA) dysregulation in the early stages of 
      hepatocarcinogenesis are hampered by the difficulty of diagnosing early lesions 
      in humans. Experimental models recapitulating human hepatocellular carcinoma 
      (HCC) are then used to perform this analysis. We performed miRNA and gene 
      expression profiling to characterize the molecular events involved in the 
      multistep process of hepatocarcinogenesis in the resistant-hepatocyte rat model. 
      A high percentage of dysregulated miRNAs/genes in HCC were similarly altered in 
      early preneoplastic lesions positive for the stem/progenitor cell marker 
      cytokeratin-19, indicating that several HCC-associated alterations occur from the 
      very beginning of the carcinogenic process. Our analysis also identified 
      miRNA/gene-target networks aberrantly activated at the initial stage of 
      hepatocarcinogenesis. Activation of the nuclear factor erythroid related factor 2 
      (NRF2) pathway and up-regulation of the miR-200 family were among the most 
      prominent changes. The relevance of these alterations in the development of HCC 
      was confirmed by the observation that NRF2 silencing impaired while miR-200a 
      overexpression promoted HCC cell proliferation in vitro. Moreover, T3-induced in 
      vivo inhibition of the NRF2 pathway accompanied the regression of 
      cytokeratin-19-positive nodules, suggesting that activation of this transcription 
      factor contributes to the onset and progression of preneoplastic lesions towards 
      malignancy. The finding that 78% of genes and 57% of dysregulated miRNAs in rat 
      HCC have been previously associated with human HCC as well underlines the 
      translational value of our results. CONCLUSION: This study indicates that most of 
      the molecular changes found in HCC occur in the very early stages of 
      hepatocarcinogenesis. Among these, the NRF2 pathway plays a relevant role and may 
      represent a new therapeutic target.
CI  - (c) 2013 by the American Association for the Study of Liver Diseases.
FAU - Petrelli, Annalisa
AU  - Petrelli A
AD  - IRCC, Institute for Cancer Research and Treatment, University of Torino School of 
      Medicine, Torino, Italy.
FAU - Perra, Andrea
AU  - Perra A
FAU - Cora, Davide
AU  - Cora D
FAU - Sulas, Pia
AU  - Sulas P
FAU - Menegon, Silvia
AU  - Menegon S
FAU - Manca, Claudia
AU  - Manca C
FAU - Migliore, Cristina
AU  - Migliore C
FAU - Kowalik, Marta Anna
AU  - Kowalik MA
FAU - Ledda-Columbano, Giovanna Maria
AU  - Ledda-Columbano GM
FAU - Giordano, Silvia
AU  - Giordano S
FAU - Columbano, Amedeo
AU  - Columbano A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131118
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (MIRN200 microRNA, rat)
RN  - 0 (MicroRNAs)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Nfe2l2 protein, rat)
SB  - IM
MH  - Animals
MH  - Carcinogenesis
MH  - Carcinoma, Hepatocellular/etiology/*metabolism
MH  - Cell Proliferation
MH  - Humans
MH  - Liver Neoplasms, Experimental/etiology/*metabolism
MH  - Male
MH  - MicroRNAs/*metabolism
MH  - NF-E2-Related Factor 2/*metabolism
MH  - Precancerous Conditions/*metabolism
MH  - Rats
MH  - Rats, Inbred F344
EDAT- 2013/07/17 06:00
MHDA- 2014/03/04 06:00
CRDT- 2013/07/17 06:00
PHST- 2013/02/18 00:00 [received]
PHST- 2013/06/29 00:00 [accepted]
PHST- 2013/07/17 06:00 [entrez]
PHST- 2013/07/17 06:00 [pubmed]
PHST- 2014/03/04 06:00 [medline]
AID - 10.1002/hep.26616 [doi]
PST - ppublish
SO  - Hepatology. 2014 Jan;59(1):228-41. doi: 10.1002/hep.26616. Epub 2013 Nov 18.