Inserm, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Equipe labellisée LNCC, Paris, France.
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.
Gut. 2016 Jun;65(6):1024-34. doi: 10.1136/gutjnl-2014-308969. Epub 2015 Mar 19.
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.
肝细胞癌（HCC）是最常见的原发性肝癌。大约三分之一的这些肿瘤存在β-连环蛋白基因的激活突变。HCC 的分子发病机制已经阐明，但死亡率仍然很高，需要新的治疗方法，包括基于 microRNAs 的治疗方法。我们旨在鉴定受β-连环蛋白调控的候选 microRNAs，这些 microRNAs可能参与肝肿瘤发生。
我们使用了一种小鼠模型，其中β-连环蛋白信号通过 tamoxifen 诱导和 Cre-Lox 介导的 APC 基因失活在肝脏中被过度激活。该模型发展出具有与人 HCC 相似特性的肿瘤。
我们发现 miR-34a 受β-连环蛋白调控，并且在小鼠肿瘤和 HCC 患者中β-连环蛋白信号的过度激活显著诱导了 miR-34a 的表达。miR-34a 的抑制剂（锁核酸，LNA-34a）在原代肝细胞培养物中发挥抗增殖活性。这种增殖抑制与细胞周期蛋白 D1 水平的降低有关，主要由 HNF-4α 协调，HNF-4α 是 miR-34a 的靶点，被认为在肝脏中作为肿瘤抑制因子发挥作用。在体内，LNA-34a 使显示β-连环蛋白激活和半胱天冬酶 2 和 3 激活的肿瘤的进展率降低约一半。
这项工作证明了 miR-34a 在具有β-连环蛋白基因突变的肝肿瘤中的关键致癌作用。我们建议，具有β-连环蛋白突变的 HCC 患者可以用 miR-34a 的抑制剂治疗。这种策略的潜在价值在于调节肿瘤抑制因子 HNF-4α，它靶向细胞周期蛋白 D1，并诱导促凋亡程序。
