A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma.
A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma.
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DOI：
10.1136/gutjnl-2012-304037
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发表时间：
2014-05
期刊：
影响因子：
24.5
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Chan TH;Lin CH;Qi L;Fei J;Li Y;Yong KJ;Liu M;Song Y;Chow RK;Ng VH;Yuan YF;Tenen DG;Guan XY;Chen L
肝细胞癌（HCC）是一种异质性肿瘤，表现出复杂的遗传和表观遗传变化。在人类癌症中，异常的转录后修饰，如选择性剪接和RNA编辑，可能导致肿瘤特异性转录组多样性。通过利用三对HCC临床标本及其邻近的非肿瘤（NT）组织对应物的大规模转录组测序，我们发现转录物中平均有20 007个推断的A到I（腺苷到肌苷）RNA编辑事件。在临床标本、细胞模型和小鼠中研究了双链RNA特异性阿达尔（Adenosine DeAminase that act on RNA）家族成员（ADARs）的作用和改变的基因特异性编辑模式。HCC显示出严重破坏的A至I RNA编辑平衡。ADAR 1和ADAR 2通过其在HCC中与NT肝组织相比的差异表达来操纵HCC的A到I失衡。肿瘤中ADAR1过表达和ADAR2下调的患者表现出肝硬化和术后复发的风险增加，并且预后差。由于ADAR 1和ADAR 2在肿瘤中的差异表达，FLNB（filamin B，β）的超编辑和COPA（coatomer protein complex，subunit α）的低编辑所反映的基因特异性编辑活性的改变与HCC的发病密切相关。体外和体内功能试验证明，ADAR 1作为癌基因发挥作用，而ADAR 2在HCC中具有肿瘤抑制能力。这些发现强调了这样一个事实，即肿瘤中差异表达的ADAR，这是导致A到I编辑失衡的原因，对HCC具有很大的预后价值和诊断潜力。
Hepatocellular carcinoma (HCC) is a heterogeneous tumour displaying a complex variety of genetic and epigenetic changes. In human cancers, aberrant post-transcriptional modifications, such as alternative splicing and RNA editing, may lead to tumour specific transcriptome diversity. By utilising large scale transcriptome sequencing of three paired HCC clinical specimens and their adjacent non-tumour (NT) tissue counterparts at depth, we discovered an average of 20 007 inferred A to I (adenosine to inosine) RNA editing events in transcripts. The roles of the double stranded RNA specific ADAR (Adenosine DeAminase that act on RNA) family members (ADARs) and the altered gene specific editing patterns were investigated in clinical specimens, cell models and mice. HCC displays a severely disrupted A to I RNA editing balance. ADAR1 and ADAR2 manipulate the A to I imbalance of HCC via their differential expression in HCC compared with NT liver tissues. Patients with ADAR1 overexpression and ADAR2 downregulation in tumours demonstrated an increased risk of liver cirrhosis and postoperative recurrence and had poor prognoses. Due to the differentially expressed ADAR1 and ADAR2 in tumours, the altered gene specific editing activities, which was reflected by the hyper-editing of FLNB (filamin B, β) and the hypo-editing of COPA (coatomer protein complex, subunit α), are closely associated with HCC pathogenesis. In vitro and in vivo functional assays prove that ADAR1 functions as an oncogene while ADAR2 has tumour suppressive ability in HCC. These findings highlight the fact that the differentially expressed ADARs in tumours, which are responsible for an A to I editing imbalance, has great prognostic value and diagnostic potential for HCC.
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影响因子：
64.8
作者：
Burns, CM;Chu, H;Emeson, RB
通讯作者：
Emeson, RB
DOI：
10.1126/science.1207018
发表时间：
2011-07-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li M;Wang IX;Li Y;Bruzel A;Richards AL;Toung JM;Cheung VG
通讯作者：
Cheung VG
影响因子：
16.6
作者：
Nishikura K
通讯作者：
Nishikura K
影响因子：
254.7
作者：
Parkin, DM;Bray, F;Pisani, P
通讯作者：
Pisani, P
影响因子：
4.8
作者：
Cenci, Caterina;Barzotti, Rita;Gallo, Angela
通讯作者：
Gallo, Angela