乙肝慢性感染與肝癌發(fā)生密切相關(guān)，我國(guó)肝癌患者絕大多數(shù)感染慢性乙肝，目前乙肝引發(fā)肝癌的機(jī)制普遍認(rèn)為是慢性炎癥、病毒X蛋白等因素,。
中科院微生物研究所孟頌東課題組李長(zhǎng)菲、王彥中等人研究發(fā)現(xiàn),，乙肝病毒mRNA也可能參與慢性乙肝感染向肝癌的轉(zhuǎn)化,，大量表達(dá)冗余的病毒mRNA與肝細(xì)胞中的小RNA miR-122結(jié)合，以“海綿”吸附的方式抑制miR-122,，進(jìn)而導(dǎo)致miR-122靶基因PBF（PTTG1 binding factor）的上調(diào),，促進(jìn)肝細(xì)胞癌變和生長(zhǎng),。
眾所周知,，mRNA的功能主要是翻譯蛋白，病毒mRNA還可通過(guò)模式識(shí)別激活天然免疫,。李長(zhǎng)菲,、王彥中等人的研究提示mRNA的新作用機(jī)制，即通過(guò)與宿主小RNA互作,，可能直接參與腫瘤發(fā)生,。
上述研究已在線發(fā)表在Journal of Virology上，這是該課題組2012年發(fā)表的第三篇相關(guān)論文,，前兩篇論文研究炎癥因子對(duì)miR-122水平的調(diào)節(jié)及miR-122對(duì)乙肝病毒復(fù)制的抑制,，分別發(fā)表在Journal of Virology和Hepatology。以上三篇研究論文勾畫(huà)出了乙肝感染引發(fā)肝癌的新機(jī)制，病毒因子（mRNA）和慢性炎癥下調(diào)肝細(xì)胞中的關(guān)鍵小RNA miR-122,，miR-122的下調(diào)一方面使病毒復(fù)制增強(qiáng),，另一方面活化腫瘤基因PBF/PTTG1從而引發(fā)肝癌，提示miR-122可作為治療乙肝及肝癌的靶點(diǎn),。(生物谷Bioon.com)
doi: 10.1128/JVI.02831-12
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HBV mRNAs-mediated miR-122 inhibition up-regulates PTTG1-binding protein which promotes HCC tumor growth and cell invasion
Changfei Li1, Yanzhong Wang1, Saifeng Wang1, Bo Wu1, Junli Hao1, Hongxia Fan1, Ying Ju1, Yuping Ding2, Lizhao Chen1, Xiaoyu Chu1, Wenjun Liu1, Xin Ye1 and Songdong Meng1,*
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. In this study, we provide evidence that all HBV mRNAs harboring a 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 (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 up-regulated in chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC). Over-expression and knock-down 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 mRNAs-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.
