Antitumour activity of an inhibitor of miR-34a in liver cancer with β-catenin-mutations
Antitumour activity of an inhibitor of miR-34a in liver cancer with β-catenin-mutations
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DOI：
10.1136/gutjnl-2014-308969
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发表时间：
2016-06-01
期刊：
影响因子：
24.5
通讯作者：
Colnot, Sabine
中科院分区：
文献类型：
--
作者：
Gougelet, Angelique;Sartor, Chiara;Colnot, Sabine
目的肝细胞癌（HCC）是最常见的原发性肝脏肿瘤。这些肿瘤中约有三分之一存在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microRNA的治疗。我们的目的是确定候选microRNA，β-连环蛋白调节，可能参与肝脏tumorigenes.Design我们使用了一个小鼠模型，其中β-连环蛋白信号被过度激活，只在肝脏中的他莫昔芬诱导和Cre-Lox介导的失活的APC基因。该模型开发的肿瘤具有类似于人类HCC.Results的特性，我们发现miR-34 a受β-catenin调控，并在小鼠肿瘤和HCC患者中由β-catenin信号过度激活显著诱导。miR-34 a（锁核酸，LNA-34 a）的抑制剂在肝细胞的原代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-4 α协调，HNF-4 α是miR-34 a的靶点，被认为是肝脏中的肿瘤抑制因子。在体内，LNA-34 a可使β-catenin激活并同时激活caspase 2和caspase 3的肿瘤的进展率降低约一半。结论本研究证实了miR-34 a在β-catenin基因突变的肝肿瘤中的关键致癌作用。我们认为，诊断为HCC且伴有β-连环蛋白突变的患者可以使用miR-34 a抑制剂进行治疗。这种策略的潜在价值在于调节肿瘤抑制因子HNF-4 α（其靶向细胞周期蛋白D1）和诱导促凋亡程序。
Objective Hepatocellular carcinoma (HCC) is the most prevalent primary tumour of the liver. About a third of these tumours presents activating mutations of the beta-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 beta-catenin, potentially involved in liver tumorigenesis.Design We used a mouse model, in which beta-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 beta-catenin, and significantly induced by the overactivation of beta-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-4 alpha, 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 beta-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 beta-catenin gene mutations. We suggest that patients diagnosed with HCC with beta-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-4 alpha, which targets cyclin D1, and the induction of a proapoptotic programme.