B肝病毒基因介导的miR-122的抑制上调的PTTG1-结合蛋白，从

StephenW

http://jvi.asm.org/content/87/4/2193.abstract?etoc
Hepatitis B Virus mRNA-Mediated miR-122 Inhibition Upregulates PTTG1-Binding Protein, Which Promotes Hepatocellular Carcinoma Tumor Growth and Cell Invasion                                                

• Changfei Lia,
• Yanzhong Wanga,
• Saifeng Wanga,
• Bo Wua,
• Junli Haoa,
• Hongxia Fana,
• Ying Jua,
• Yuping Dingb,
• Lizhao Chena,
• Xiaoyu Chua,
• Wenjun Liua,
• Xin Yea and
• Songdong Menga
  

- Author Affiliations

                  

• aCAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS),                           Beijing, China
• bYantai City Hospital for Infectious Diseases, Yantai, Shandong, China
  

               
ABSTRACT                  

As the most abundant liver-specific microRNA, miR-122 is involved in diverse aspects of hepatic function and neoplastic transformation. Our previous study showed that miR-122 levels are significantly decreased in hepatitis B virus (HBV)-infected patients, which may facilitate viral replication and persistence (S. Wang, L. Qiu, X. Yan, W. Jin, Y. Wang, L. Chen, E. Wu, X. Ye, G. F. Gao, F. Wang, Y. Chen, Z. Duan, and S. Meng, Hepatology 55:730–741, 2012). Loss of miR-122 expression in patients with hepatitis B enhances hepatitis B virus replication through cyclin G1-modulated P53 activity.). In this study, we provide evidence that all HBV mRNAs harboring an miR-122 complementary site act as sponges to bind and sequester endogenous miR-122, indicating that the highly redundant HBV transcripts are involved in HBV-mediated miR-122 suppression. We next identified pituitary tumor-transforming gene 1 (PTTG1) binding factor (PBF) as a target of miR-122 and demonstrated that HBV replication causes an obvious increase in PBF levels. Furthermore, we observed that the miR-122 levels were decreased and PBF was upregulated in chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC). Overexpression and knockdown studies both revealed that PBF enhances proliferation and invasion of HCC cells, and silencing PBF resulted in a dramatic reduction of HCC tumor growth in vivo. Mechanistic analysis demonstrated that PBF interacts with PTTG1 and facilitates PTTG1 nuclear translocation, subsequently increasing its transcriptional activities. Therefore, we identified a novel HBV mRNA-miR-122-PBF regulatory pathway that facilitates  malignant hepatocyte growth and invasion in CHB which may contribute to CHB-induced HCC development and progression. Our work underscores the reciprocal interplay of host miRNA sequestration and depletion by viral mRNAs, which may contribute to chronic-infection-related cancer.                  

               

StephenW

摘要

最丰富的肝特定的microRNA，miR-122的涉及不同方面的肝功能及肿瘤转化。我们以前的研究表明，miR-122的水平显着下降，B型肝炎病毒（HBV）感染的患者，这可能有利于病毒的复制和持久化（王珊，L.秋，X.燕，W.进，王勇，E. L.陈武，十叶，GF高，F.王陈，Y.，Z.段，和S猛，肝脏病学55:730-741，2012）。亏损的miR-122表达的乙肝患者提高乙肝病毒的复制，通过调制细胞周期G1-P53活动）。在这项研究中，我们提供的证据，所有的HBV基因窝藏miR-122的互补海绵网站作为内源性miR-122的约束和隔离，这表明，高度冗余的的HBV转录参与乙肝病毒介导的miR-122的抑制。接下来，我们确定垂体肿瘤转化基因1（PTTG1）结合因子（PBF）为​​目标的miR-122和证明，乙肝病毒复制导致PBF水平明显增加。此外，我们发现，miR-122的水平下降和，PBF被上调在慢性乙型肝炎（CHB）和肝细胞癌（HCC）。表达和敲除研究都显示，PBF增强对肝癌细胞的增殖和侵袭能力，，和沉默PBF在HCC肿瘤生长显着减少。机理分析表明，PBF互动与PTTG1和促进PTTG1核转位，并增加其转录活动。因此，我们确定了新的HBV表达的miR-122-PBF的监管途径，有利于恶性慢性乙型肝炎肝细胞生长和侵袭，这可能有助于慢性乙肝引起的肝癌的发生和发展。我们的工作强调了相互相互作用的主机miRNA的封存和病毒的mRNA的消耗，这可能会导致慢性感染相关的癌症。

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HBV>PBF>NT5C3>miR-122>HCC&HBV