Antitumor activity of an inhibitor of miR-34a in liver cancer with β-catenin-mutations miR-34a oncogenicity in β-catenin-mutated liver cancerReport as inadecuate




Antitumor activity of an inhibitor of miR-34a in liver cancer with β-catenin-mutations miR-34a oncogenicity in β-catenin-mutated liver cancer - Download this document for free, or read online. Document in PDF available to download.

* Corresponding author 1 Institut Cochin 2 Imagerie du petit animal 3 BIP-D - Plate Forme Paris Descartes de Bioinformatique 4 Service d-Anatomie et de cytologie pathologiques Cochin

Abstract : Objective: Hepatocellular carcinoma HCC is the most prevalent primary tumor of the liver. About a third of these tumors 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 signaling was overactivated exclusively in the liver, by the tamoxifen-inducible and Cre-Lox-mediated inactivation of the Apc gene. This model develops tumors 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 signaling in mouse tumors and in HCC patients. An inhibitor of miR-34a LNA-34a exerted anti-proliferative 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 tumor suppressor in the liver. In vivo, LNA-34a approximately halved progression rates for tumors displaying β-catenin activation together with an activation of caspases 2 and 3. Conclusion: This work demonstrates the key oncogenic role of miR-34a in liver tumors 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 tumor suppressor HNF-4α, which targets cyclin D1, and the induction of a pro-apoptotic program.

Keywords : HNF-4α hepatocellular carcinoma β-catenin miR-34a miRNA-based therapies





Author: Angélique Gougelet - Chiara Sartor - Laura Bachelot - Cécile Godard - Carmen Marchiol - Gilles Renault - Frédéric Tores - Pat

Source: https://hal.archives-ouvertes.fr/



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