title: MicroRNA-425-3p predicts response to sorafenib therapy in patients with hepatocellular carcinoma.
abstract: OBJECTIVE
  Sorafenib is the standard of care in advanced hepatocellular carcinoma (HCC), however no criteria have been established to select patients likely to benefit from this therapy. In this study, we evaluated the predictive role of microRNAs (miRNAs) in this setting of patients.
  
  
  METHODS
  We profiled 522 miRNA in a series of 26 HCC patients treated with sorafenib (training set) and validated the results in an independent series of 58 patients (validation set). Formalin-fixed paraffin-embedded tumour and cirrhotic liver biopsies were used for RNA extraction and miRNAs profiling with TaqMan Arrays technology. Statistical analyses were used to correlate miRNA levels with clinical outcome, including time to progression (TTP), progression free (PFS), and overall survival. Cell viability and cell motility of HuH-7 or HepG2 HCC cells were tested in vitro after transfection with specific miRNA precursor, inhibitor or controls and sorafenib treatment.
  
  
  RESULTS
  Six miRNAs were significantly associated with clinical variables in the training set and only miR-425-3p could be further validated. Higher levels of miR-425-3p were associated with longer TTP and PFS (P = 0.0008; HR = 0.4; 95% CI = 0.2-0.7 and P = 0.007; HR = 0.5; 95% CI = 0.3-0.9 respectively). Multivariate analysis confirmed the predictive significance of miR-425-3p. Furthermore, an association between increased miR-425-3p, cell death and reduced cell motility was defined in vitro in HCC cell lines treated with sorafenib.
  
  
  CONCLUSIONS
  Assessment of miR-425-3p levels in liver biopsies could help in stratifying patients with advanced HCC for sorafenib treatment. These promising results need to be confirmed in a large prospective study.
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vaira
authors.forename: Massimo
authors.initials: M
authors.lastname: Roncalli
authors.forename: Carlo
authors.initials: C
authors.lastname: Carnaghi
authors.forename: Alice
authors.initials: A
authors.lastname: Faversani
authors.forename: Marco
authors.initials: M
authors.lastname: Maggioni
authors.forename: Claudia
authors.initials: C
authors.lastname: Augello
authors.forename: Lorenza
authors.initials: L
authors.lastname: Rimassa
authors.forename: Tiziana
authors.initials: T
authors.lastname: Pressiani
authors.forename: Gaia
authors.initials: G
authors.lastname: Spagnuolo
authors.forename: Luca
authors.initials: L
authors.lastname: Di Tommaso
authors.forename: Stefano
authors.initials: S
authors.lastname: Fagiuoli
authors.forename: Elena
authors.initials: E
authors.lastname: Rota Caremoli
authors.forename: Massimo
authors.initials: M
authors.lastname: Barberis
authors.forename: Roberto
authors.initials: R
authors.lastname: Labianca
authors.forename: Armando
authors.initials: A
authors.lastname: Santoro
authors.forename: Silvano
authors.initials: S
authors.lastname: Bosari
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D016022:Case-Control Studies; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C555677:MIRN425 microRNA, human; D035683:MicroRNAs; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib
keywords: hepatocellular carcinoma; liver; microRNAs; sorafenib