Article Text

PDF
Original article
Antitumour activity of an inhibitor of miR-34a in liver cancer with β-catenin-mutations
  1. Angélique Gougelet1,2,3,4,
  2. Chiara Sartor1,2,3,4,
  3. Laura Bachelot1,2,3,4,
  4. Cécile Godard1,2,3,4,
  5. Carmen Marchiol1,2,3,5,
  6. Gilles Renault1,2,3,5,
  7. Frédéric Tores6,
  8. Patrick Nitschke6,
  9. Catherine Cavard1,2,3,4,
  10. Benoit Terris1,2,3,4,7,
  11. Christine Perret1,2,3,4,
  12. Sabine Colnot1,2,3,4
  1. 1Inserm, U1016, Institut Cochin, Paris, France
  2. 2CNRS, UMR8104, Paris, France
  3. 3Université Paris Descartes, Sorbonne Paris Cité, Paris, France
  4. 4Equipe labellisée LNCC, Paris, France
  5. 5Imagerie du petit animal, Institut Cochin, Paris, France
  6. 6Plateforme de bioinformatique Paris Descartes, Institut Imagine, Paris, France
  7. 7Service d'Anatomie et Cytologie Pathologiques, AP-HP, Hôpital Cochin, Université Paris Descartes, Paris, France
  1. Correspondence to Angélique Gougelet Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, 24, rue du Faubourg Saint Jacques, Paris 75014, France; Angelique.gougelet{at}inserm.fr

Abstract

Objective 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.

Design 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.

Results 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.

Conclusions 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.

  • CANCER
  • CELL SIGNALLING
  • HEPATOCELLULAR CARCINOMA
  • LIVER
  • MOLECULAR ONCOLOGY

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.