Hepatitis B core protein promotes liver cancer metastasis through miR-382-5p/DLC-1 axis
Hepatitis B core protein promotes liver cancer metastasis through miR-382-5p/DLC-1 axis
复制标题
乙型肝炎核心蛋白通过miR-382-5p/DLC-1轴促进肝癌转移。
DOI：
10.1016/j.bbamcr.2017.09.020
复制
发表时间：
2018-01-01
影响因子：
5.1
通讯作者：
Liang, Xiaohong
中科院分区：
文献类型：
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作者：
Du, Juan;Bai, Fuxiang;Liang, Xiaohong
乙型肝炎病毒核心蛋白（HBc），也被称为核心抗原，因其在病毒衣壳形成和病毒复制中的关键作用而闻名。近年来，研究表明，HBc具有通过调节宿主基因表达来控制细胞生物学活性的潜力。本研究中，我们利用miRNA微阵列技术鉴定了hbc表达的HCC细胞中24个上调的miRNA和21个下调的miRNA，这些miRNA参与了包括细胞运动在内的多个生物学过程。体外transwell实验和体内尾静脉注射模型一致显示HBc促进HCC转移。此外，mirna靶基因网络分析显示，肝癌中缺失（DLC-1）基因是一个重要的细胞运动负调控因子，在hbc引入的细胞中可能被几种差异表达的mirna靶向。引入miRNAs模拟物或抑制剂和3' utr荧光素酶活性测定证明，miR-382-5p有效抑制DLC-1表达及其3'-UTR荧光素酶报告细胞活性。重要的是，miR-382-5p模拟物/抑制剂和DLC-1表达载体的共转染几乎消除了HBc对细胞运动的促进作用，这表明miR-382-5p/DLC-1轴对于介导HBc增强的HCC运动很重要。临床HCC样本中miR-382-5p与DLC-1表达水平也呈负相关。此外，hbc阳性HCC组织中miR-382-5p水平升高，DLC-1表达降低。总之，我们的研究结果表明，HBc通过调节miR-382-5p/DLC-1轴促进HCC的运动，这可能为临床诊断和治疗提供新的靶点。
The hepatitis B virus core protein (HBc), also named core antigen, is well-known for its key role in viral capsid formation and virus replication. Recently, studies showed that HBc has the potential to control cell biology activity by regulating host gene expression. Here, we utilized miRNA microarray to identify 24 upregulated miRNAs and 21 downregulated miRNAs in HBc-expressed HCC cells, which were involved in multiple biological processes, including cell motility. Consistently, the in vitro transwell assay and the in vivo tail-vein injection model showed HBc promotion on HCC metastasis. Further, the miRNA-target gene network analysis displayed that the deleted in liver cancer (DLC-1) gene, an important negative regulator for cell motility, was potentially targeted by several differentially expressed miRNAs in HBc-introduced cells. Introduction of miRNAs mimics or inhibitors and 3'UTR luciferase activity assay proved that miR-382-5p efficiently suppressed DLC-1 expression and its 3'-UTR luciferase reporter activity. Importantly, cotransfection of miR-382-5p mimics/inhibitors and the DLC-1 expression vector almost abrogated HBc promotion on cell motility, indicating that the miR-382-5p/DLC-1 axis is important for mediating HBc-enhanced HCC motility. Clinical HCC samples also showed a negative correlation between miR-382-5p and DLC-1 expression level. Furthermore, HBc-positive HCC tissues showed high miR-382-5p level and reduced DLC-1 expression. In conclusion, our findings revealed that HBc promoted HCC motility by regulating the miR-382-5p/DLC-1 axis, which might provide a novel target for clinical diagnosis and treatment.