title: Bioinformatics approach to predict target genes for dysregulated microRNAs in hepatocellular carcinoma: study on a chemically-induced HCC mouse model.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is an aggressive epithelial tumor which shows very poor prognosis and high rate of recurrence, representing an urgent problem for public healthcare. MicroRNAs (miRNAs/miRs) are a class of small, non-coding RNAs that attract great attention because of their role in regulation of processes such as cellular growth, proliferation, apoptosis. Because of the thousands of potential interactions between a single miR and target mRNAs, bioinformatics prediction tools are very useful to facilitate the task for individuating and selecting putative target genes. In this study, we present a chemically-induced HCC mouse model to identify differential expression of miRNAs during the progression of the hepatic injury up to HCC onset. In addition, we describe an established bioinformatics approach to highlight putative target genes and protein interaction networks where they are involved.
  
  
  RESULTS
  We describe four miRs (miR-125a-5p, miR-27a, miR-182, miR-193b) which showed to be differentially expressed in the chemically-induced HCC mouse model. The miRs were subjected to four of the most used predictions tools and 15 predicted target genes were identified. The expression of one (ANK3) among the 15 predicted targets was further validated by immunoblotting. Then, enrichment annotation analysis was performed revealing significant clusters, including some playing a role in ion transporter activity, regulation of receptor protein serine/threonine kinase signaling pathway, protein import into nucleus, regulation of intracellular protein transport, regulation of cell adhesion, growth factor binding, and regulation of TGF-beta/SMAD signaling pathway. A network construction was created and links between the selected miRs, the predicted targets as well as the possible interactions among them and other proteins were built up.
  
  
  CONCLUSIONS
  In this study, we combined miRNA expression analysis, obtained by an in vivo HCC mouse model, with a bioinformatics-based workflow. New genes, pathways and protein interactions, putatively involved in HCC initiation and progression, were identified and explored.
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio, Coppito 2, 67100, L'Aquila, Italy. filippo.delvecchio1@graduate.univaq.it.
authors.forename: Filippo
authors.initials: F
authors.lastname: Del Vecchio
authors.affiliation: Department of Computer Engineering and Science, and Mathematics, University of L'Aquila, Via Vetoio, Coppito 1, L'Aquila, 67100, Italy. francesco.gallo@univaq.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Gallo
authors.affiliation: Department of Computer Engineering and Science, and Mathematics, University of L'Aquila, Via Vetoio, Coppito 1, L'Aquila, 67100, Italy. antinisca.dimarco@univaq.it.
authors.forename: Antinisca
authors.initials: A
authors.lastname: Di Marco
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio, Coppito 2, 67100, L'Aquila, Italy. valentina.mastroiaco@graduate.univaq.it.
authors.forename: Valentina
authors.initials: V
authors.lastname: Mastroiaco
authors.affiliation: Department of Computer Engineering and Science, and Mathematics, University of L'Aquila, Via Vetoio, Coppito 1, L'Aquila, 67100, Italy. pasquale.caianiello@di.univaq.it.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Caianiello
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio, Coppito 2, 67100, L'Aquila, Italy. francesca.zazzeroni@univaq.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Zazzeroni
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio, Coppito 2, 67100, L'Aquila, Italy. edoardo.alesse@univaq.it.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Alesse
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio, Coppito 2, 67100, L'Aquila, Italy. alessandra.tessitore@univaq.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tessitore
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D019295:Computational Biology / Q000379:methods*; D053263:Gene Regulatory Networks; D008113:Liver Neoplasms / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D060066:Protein Interaction Maps; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger