title: 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).
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: IRCC, Institute for Cancer Research and Treatment, University of Torino School of Medicine, Torino, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Petrelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Perra
authors.forename: Davide
authors.initials: D
authors.lastname: Cora
authors.forename: Pia
authors.initials: P
authors.lastname: Sulas
authors.forename: Silvia
authors.initials: S
authors.lastname: Menegon
authors.forename: Claudia
authors.initials: C
authors.lastname: Manca
authors.forename: Cristina
authors.initials: C
authors.lastname: Migliore
authors.forename: Marta Anna
authors.initials: MA
authors.lastname: Kowalik
authors.forename: Giovanna Maria
authors.initials: GM
authors.lastname: Ledda-Columbano
authors.forename: Silvia
authors.initials: S
authors.lastname: Giordano
authors.forename: Amedeo
authors.initials: A
authors.lastname: Columbano
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000378:metabolism*; D049109:Cell Proliferation; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011230:Precancerous Conditions / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: C555600:MIRN200 microRNA, rat; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat