title: Antitumour activity of an inhibitor of miR-34a in liver cancer with β-catenin-mutations.
abstract: Hepatocellular carcinoma (HCC) is the most prevalent primary tumour of the liver. About a third of these tumours presents activating mutations of the β-catenin gene. The molecular pathogenesis of HCC has been elucidated, but mortality remains high, and new therapeutic approaches, including treatments based on microRNAs, are required. We aimed to identify candidate microRNAs, regulated by β-catenin, potentially involved in liver tumorigenesis.
  
  
  
  We used a mouse model, in which β-catenin signalling was overactivated exclusively in the liver by the tamoxifen-inducible and Cre-Lox-mediated inactivation of the Apc gene. This model develops tumours with properties similar to human HCC.
  
  
  
  We found that miR-34a was regulated by β-catenin, and significantly induced by the overactivation of β-catenin signalling in mouse tumours and in patients with HCC. An inhibitor of miR-34a (locked nucleic acid, LNA-34a) exerted antiproliferative activity in primary cultures of hepatocyte. This inhibition of proliferation was associated with a decrease in cyclin D1 levels, orchestrated principally by HNF-4α, a target of miR-34a considered to act as a tumour suppressor in the liver. In vivo, LNA-34a approximately halved progression rates for tumours displaying β-catenin activation together with an activation of caspases 2 and 3.
  
  
  
  This work demonstrates the key oncogenic role of miR-34a in liver tumours with β-catenin gene mutations. We suggest that patients diagnosed with HCC with β-catenin mutations could be treated with an inhibitor of miR-34a. The potential value of this strategy lies in the modulation of the tumour suppressor HNF-4α, which targets cyclin D1, and the induction of a proapoptotic programme.
authors: Inserm, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Equipe labellisée LNCC, Paris, France.
authors: Angélique
authors: A
authors: Gougelet
authors: Inserm, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Equipe labellisée LNCC, Paris, France.
authors: Chiara
authors: C
authors: Sartor
authors: Inserm, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Equipe labellisée LNCC, Paris, France.
authors: Laura
authors: L
authors: Bachelot
authors: Inserm, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Equipe labellisée LNCC, Paris, France.
authors: Cécile
authors: C
authors: Godard
authors: Inserm, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Imagerie du petit animal, Institut Cochin, Paris, France.
authors: Carmen
authors: C
authors: Marchiol
authors: Inserm, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Imagerie du petit animal, Institut Cochin, Paris, France.
authors: Gilles
authors: G
authors: Renault
authors: Plateforme de bioinformatique Paris Descartes, Institut Imagine, Paris, France.
authors: Frédéric
authors: F
authors: Tores
authors: Plateforme de bioinformatique Paris Descartes, Institut Imagine, Paris, France.
authors: Patrick
authors: P
authors: Nitschke
authors: Inserm, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Equipe labellisée LNCC, Paris, France.
authors: Catherine
authors: C
authors: Cavard
authors: Inserm, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Equipe labellisée LNCC, Paris, France Service d'Anatomie et Cytologie Pathologiques, AP-HP, Hôpital Cochin, Université Paris Descartes, Paris, France.
authors: Benoit
authors: B
authors: Terris
authors: Inserm, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Equipe labellisée LNCC, Paris, France.
authors: Christine
authors: C
authors: Perret
authors: Inserm, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Equipe labellisée LNCC, Paris, France.
authors: Sabine
authors: S
authors: Colnot
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000628:therapy; D019938:Cyclin D1 / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000628:therapy; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000628:therapy; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics*; D009154:Mutation; D051176:beta Catenin / Q000235:genetics*
chemical_list: C530105:Ccnd1 protein, mouse; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D051176:beta Catenin; D019938:Cyclin D1
keywords: CANCER; CELL SIGNALLING; HEPATOCELLULAR CARCINOMA; LIVER; MOLECULAR ONCOLOGY