Hepatitis B virus mRNAs functionally sequester let-7a and enhance hepatocellular carcinoma
Hepatitis B virus mRNAs functionally sequester let-7a and enhance hepatocellular carcinoma
复制标题
乙型肝炎病毒 mRNA 功能性隔离 let-7a 并增强肝细胞癌
DOI：
10.1016/j.canlet.2016.09.028
复制
发表时间：
2016-12-01
期刊：
影响因子：
9.7
通讯作者：
Meng, Songdong
中科院分区：
文献类型：
--
作者：
Deng, Mengmeng;Hou, Junwei;Meng, Songdong
肝炎)3病毒（HBV）感染可诱导肝癌发生和恶性进展，但感染过程中产生的冗余病毒mrna的全球影响尚不清楚。本研究通过microRNA （miRNA）靶标预测和全基因组表达分析发现，HBV pre-C/C mRNA可导致多个let-7a靶向基因上调。然后在HBV前csc，前S和S mrna中鉴定了HBV基因组中nt 86至108的let-7a互补区域。在转染和病毒感染情况下观察到HBV mrna对let-7a的隔离作用，这种隔离作用依赖于let-7a的应答序列。此外，我们发现AGO2结合减少，let-7a靶点（如c-myc、K-RAS和CCR7）在病毒mRNA表达时功能mRNA和蛋白去抑制。肝细胞癌（HCC）合并HBV感染患者肝脏中Let-7a水平显著降低，且与肝内pre-S2 mRNA水平呈负相关。最后，体外和体内研究均表明，HBV mrna抑制let-7a可增强HCC细胞集落形成和肿瘤生长，这为HBV mrna的致癌潜力提供了证据。2016爱思唯尔爱尔兰有限公司版权所有。
Hepatitis)3 virus (HBV) infection induces hepatocarcinogenesis and malignant progression, yet global effects of the redundant viral mRNAs produced during infection are unexplored. Here, microRNA (miRNA) target prediction and whole genome expression analysis revealed that HBV pre-C/C mRNA leads to upregulation of multiple let-7a targeted genes. A let-7a complementary region from nt 86 to 108 in the HBV genome was then identified in HBV pre-CSC, pre-S, and S mRNAs. The let-7a sequestration effect by HBV mRNAs was observed under transfection and virus infection, which is dependent on the let-7a response sequence. Moreover, we found reduced AGO2 binding, as well as functional mRNA and protein de-repression of let-7a targets (e.g., c-myc, K-RAS, and CCR7), upon viral mRNA expression. Let-7a levels in the liver were significantly decreased in hepatocellular carcinoma (HCC) patients with HBV infection and were negatively correlated with intrahepatic pre-S2 mRNA levels. Finally, both in vitro and in vivo studies demonstrated that let-7a inhibition by HBV mRNAs resulted in enhanced HCC cell colony formation and tumor growth, providing evidence of the oncogenic potential of HBV mRNAs. (C) 2016 Elsevier Ireland Ltd. All rights reserved.