title: MicroRNA-221 targets Bmf in hepatocellular carcinoma and correlates with tumor multifocality.
abstract: Deregulated cell proliferation and apoptosis play a major role in hepatocellular carcinoma (HCC). MicroRNAs participate in the modulation of key molecules linked to hepatocarcinogenesis.
  
  
  OBJECTIVE
  This study aims to investigate the role of miR-221 in the modulation of Bmf, a proapoptotic BH3-only protein, and to characterize miR-221 contribution to hepatocarcinogenesis through modulation of apoptosis.
  
  
  METHODS
  Transfection of miR-221 and anti-miR-221 in HCC-derived cell lines and luciferase reporter assay were used to assess Bmf as a target of miR-221. Modulation of miR-221 and Bmf expression contributed to characterize their role in anoikis. Primary HCC tissues were analyzed to assess the clinical relevance of in vitro findings.
  
  
  RESULTS
  Enforced miR-221 expression caused Bmf down-regulation, whereas anti-miR-221 induced its up-regulation. A luciferase reporter assay confirmed Bmf as a target of miR-221. Following matrix detachment, miR-221 silencing led to increased apoptotic cell death. The analysis of HCC tissues revealed an inverse correlation between miR-221 and Bmf expression and a direct correlation between Bmf and activated caspase-3, as a marker of apoptosis. High miR-221 levels were associated with tumor multifocality and reduced time to recurrence after surgery.
  
  
  CONCLUSIONS
  Our results indicate that miR-221, by targeting Bmf, inhibits apoptosis. Moreover, in HCC, miR-221 overexpression is associated with a more aggressive phenotype. These findings, together with the previously reported modulation of CDKN1B/p27 and CDKN1C/p57, show that miR-221 simultaneously affects multiple pro-oncogenic pathways and suggest miR-221 as a potential target for nonconventional treatment against HCC.
authors: Dipartimento di Medicina Interna e Gastroenterologia e Centro di Ricerca Biomedica Applicata, Università di Bologna, Bologna, Italy. laura.gramantieri@aosp.bo.it
authors: Laura
authors: L
authors: Gramantieri
authors: Francesca
authors: F
authors: Fornari
authors: Manuela
authors: M
authors: Ferracin
authors: Angelo
authors: A
authors: Veronese
authors: Silvia
authors: S
authors: Sabbioni
authors: George Adrian
authors: GA
authors: Calin
authors: Gian Luca
authors: GL
authors: Grazi
authors: Carlo Maria
authors: CM
authors: Croce
authors: Luigi
authors: L
authors: Bolondi
authors: Massimo
authors: M
authors: Negrini
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018390:Gene Targeting; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000502:physiology*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009378:Neoplasms, Multiple Primary / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D035683:MicroRNAs; D034741:RNA, Small Interfering; C486655:BMF protein, human; C525709:MIR221, human