Angélique Gougelet1, Chiara Sartor1, Laura Bachelot1, Cécile Godard1, Carmen Marchiol2, Gilles Renault2, Frédéric Tores3, Patrick Nitschke3, Catherine Cavard1, Benoit Terris4, Christine Perret1, Sabine Colnot1. 1. Inserm, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Equipe labellisée LNCC, Paris, France. 2. 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. 3. Plateforme de bioinformatique Paris Descartes, Institut Imagine, Paris, France. 4. 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.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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 mousetumours 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/