A Small-Molecule Modulator of the Tumor-Suppressor miR34a Inhibits the Growth of Hepatocellular Carcinoma
A Small-Molecule Modulator of the Tumor-Suppressor miR34a Inhibits the Growth of Hepatocellular Carcinoma
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肿瘤抑制因子 miR34a 的小分子调节剂抑制肝细胞癌的生长
DOI：
10.1158/0008-5472.can-14-0855
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发表时间：
2014-11-01
期刊：
影响因子：
11.2
通讯作者：
Chen, Yangchao
中科院分区：
文献类型：
--
作者：
Xiao, Zhangang;Li, Chi Han;Chen, Yangchao
恢复肿瘤中下调的生长抑制microRNA（miRNA）表达的小分子可能具有作为抗癌剂的潜力。miR 34 a作为肿瘤抑制因子发挥作用，并且通常在多种人类癌症（包括肝细胞癌（HCC））中下调或沉默。在这项研究中，我们使用了基于肝癌细胞的miR 34 a荧光素酶报告系统，筛选miR 34 a调节剂，可以发挥抗癌活性。一种被鉴定为主要候选物的化合物，称为Rubone，通过其特异性上调HCC细胞中miR 34 a的能力来鉴定。Rubone激活了野生型或突变型p53的HCC细胞中miR 34 a的表达，但在p53缺失的细胞中没有激活。值得注意的是，Rubone对非致瘤性人肝细胞缺乏生长抑制作用。在HCC的小鼠异种移植模型中，Rubone显着抑制肿瘤生长，在体外和体内均表现出比索拉非尼更强的抗HCC活性。机制研究表明，Rubone降低了细胞周期蛋白D1，Bcl-2和其他miR 34 a靶基因的表达，并增强了miR 34 a启动子上p53的占有率。总之，我们的研究结果为Rubone作为进一步研究的主要候选药物提供了临床前概念证明，作为一类基于miR 34 a肿瘤抑制功能恢复的新型HCC治疗药物。(C)2014年AACR。
Small molecules that restore the expression of growth-inhibitory microRNAs (miRNA) downregulated in tumors may have potential as anticancer agents. miR34a functions as a tumor suppressor and is downregulated or silenced commonly in a variety of human cancers, including hepatocellular carcinoma (HCC). In this study, we used an HCC cell-based miR34a luciferase reporter system to screen for miR34a modulators that could exert anticancer activity. One compound identified as a lead candidate, termed Rubone, was identified through its ability to specifically upregulate miR34a in HCC cells. Rubone activated miR34a expression inHCC cells with wildtype or mutated p53 but not in cells with p53 deletions. Notably, Rubone lacked growth-inhibitory effects on nontumorigenic human hepatocytes. In a mouse xenograft model of HCC, Rubone dramatically inhibited tumor growth, exhibiting stronger anti-HCC activity than sorafenib both in vitro and in vivo. Mechanistic investigations showed that Rubone decreased expression of cyclin D1, Bcl-2, and other miR34a target genes and that it enhanced the occupancy of p53 on the miR34a promoter. Taken together, our results offer a preclinical proof of concept for Rubone as a lead candidate for further investigation as a new class of HCC therapeutic based on restoration of miR34a tumor-suppressor function. (C) 2014 AACR.