Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
Hepatology. 2015 Feb;61(2):561-73. doi: 10.1002/hep.27491.
Growing evidence indicates that the aberrant expression of microRNAs (miRNAs) contributes to tumor development; however, the function of miRNAs in human hepatocellular carcinoma (HCC) remains largely undefined. In this study, we report that microRNA-422a (miR-422a) is significantly down-regulated in HCC tumor samples and cell lines compared with normal controls, and its expression level is negatively correlated with pathological grading, recurrence, and metastasis. The restoration of miR-422a expression in HCC tumor cells significantly inhibited cell proliferation and migration in vitro. At the same time, the overexpression of miR-422a in HCC tumor cells significantly inhibits tumor growth and liver metastasis in xenograft tumor models. A mechanistic study identified three genes, forkhead box G1 (FOXG1), FOXQ1, and FOXE1, as miR-422a targets in the regulation of HCC development. We also investigated the function of the three targets themselves in HCC tumorigenesis using RNAi manipulation and demonstrated that the knockdown of these targets led to significant inhibition of tumor cell proliferation and migration both in vitro and in vivo. More interestingly, a potential miR-422a promoter region was identified. Both the promoter activity and miR-422a expression were negatively regulated by the three targets, indicating that a double-negative feedback loop exists between miR-422a and its targets. Moreover, we explored the therapeutic potential of miR-422a in HCC treatment and found that the therapeutic delivery of miR-422a significantly inhibited tumor development in a xenograft tumor model and a diethylnitrosamine-induced primary HCC model.
Our findings show the critical roles of miR-422a and its targets--FOXG1, FOXQ1, and FOXE1--in the regulation of HCC development and provide new potential candidates for HCC therapy.
越来越多的证据表明，微小 RNA（miRNA）的异常表达有助于肿瘤的发展；然而，miRNA 在人肝癌（HCC）中的功能仍未得到充分阐明。在这项研究中，我们报告说，miR-422a 在 HCC 肿瘤样本和细胞系中与正常对照相比明显下调，其表达水平与病理分级、复发和转移呈负相关。在 HCC 肿瘤细胞中恢复 miR-422a 的表达可显著抑制细胞的体外增殖和迁移。与此同时，在 HCC 肿瘤细胞中过表达 miR-422a 可显著抑制异种移植肿瘤模型中的肿瘤生长和肝转移。一项机制研究确定了三个基因，叉头框 G1（FOXG1）、FOXQ1 和 FOXE1，作为 miR-422a 在 HCC 发展中的调节靶点。我们还使用 RNAi 操作研究了三个靶点本身在 HCC 肿瘤发生中的作用，并证明了这些靶点的敲低导致了体外和体内肿瘤细胞增殖和迁移的显著抑制。更有趣的是，确定了一个潜在的 miR-422a 启动子区域。启动子活性和 miR-422a 表达均受三个靶点的负调控，表明 miR-422a 与其靶点之间存在双负反馈回路。此外，我们探讨了 miR-422a 在 HCC 治疗中的治疗潜力，并发现 miR-422a 的治疗性传递可显著抑制异种移植肿瘤模型和二乙基亚硝胺诱导的原发性 HCC 模型中的肿瘤发展。
我们的研究结果表明，miR-422a 及其靶基因——FOXG1、FOXQ1 和 FOXE1——在 HCC 发展中的调控中起着关键作用，并为 HCC 治疗提供了新的潜在候选物。
