Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma.
Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma.
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DOI：
10.1016/j.cell.2013.02.032
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发表时间：
2013-03-28
期刊：
影响因子：
64.5
通讯作者：
Faulkner GJ
中科院分区：
文献类型：
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作者：
Shukla R;Upton KR;Muñoz-Lopez M;Gerhardt DJ;Fisher ME;Nguyen T;Brennan PM;Baillie JK;Collino A;Ghisletti S;Sinha S;Iannelli F;Radaelli E;Dos Santos A;Rapoud D;Guettier C;Samuel D;Natoli G;Carninci P;Ciccarelli FD;Garcia-Perez JL;Faivre J;Faulkner GJ
LINE-1（L1）反转录转座子是移动的遗传元件，占人类基因组的约17%。新的L1插入可以深刻地改变基因功能并导致疾病，尽管它们在癌症中的意义尚不清楚。在这里，我们应用增强型逆转录转座子捕获测序（RC-seq）19肝细胞癌（HCC）基因组，并阐明了两个原型L1介导的机制，使肿瘤发生。在第一个实施例中，4/19（21.1%）供体在结肠直肠癌（MCC）中突变的肿瘤抑制因子中呈现生殖系逆转录转座事件。在每种情况下，MCC表达被消除，从而使致癌β-连环蛋白/Wnt信号传导成为可能。在第二个实施例中，通过肿瘤特异性L1插入激活致瘤性抑制18（ST 18）。实验分析证实，L1通过阻断ST 18对其增强子的抑制来中断负反馈回路。ST 18也经常在Mdr 2 −/−小鼠的HCC结节中扩增，支持其作为候选肝癌基因的分配。这些证明的原则的结果证实L1介导的逆转录转座作为一个重要的病因因素在肝癌。肿瘤细胞中的L1动员加速HCC基因组的转化肿瘤特异性L1插入中断了调节ST 18 L1逆转录转座子的负反馈环，ST 18 L1逆转录转座子广泛存在于人类基因组中，可以动员和激活感染B型肝炎或C型肝炎病毒的个体的肝脏中的癌基因，促进肝细胞癌的发展和生长。通过L1插入鉴定的基因为癌症筛查和干预提供了新的选择。
LINE-1 (L1) retrotransposons are mobile genetic elements comprising ∼17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic β-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2−/− mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC. ► L1 retrotransposons promote tumorigenesis in hepatocellular carcinoma (HCC) ► Germline L1 and Alu insertions in MCC activate β-catenin/Wnt signaling ► L1 mobilization in tumor cells accelerates transformation of the HCC genome ► A tumor-specific L1 insertion interrupts a negative feedback loop regulating ST18 L1 retrotransposons, which are widespread in the human genome, can mobilize and activate oncogenes in the livers of individuals infected with the hepatitis B or hepatitis C virus, promoting the development and growth of hepatocellular carcinoma. Genes identified by the L1 insertions present new options for cancer screening and intervention.
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影响因子：
64.5
作者：
GRODEN, J;THLIVERIS, A;WHITE, R
通讯作者：
WHITE, R
影响因子：
4
作者：
Hancks, Dustin C.;Kazazian, Haig H., Jr.
通讯作者：
Kazazian, Haig H., Jr.
DOI：
10.1073/pnas.0831042100
发表时间：
2003-04-29
影响因子：
11.1
作者：
Brouha, B;Schustak, J;Kazazian, HH
通讯作者：
Kazazian, HH
影响因子：
64.5
作者：
Gilbert, N;Lutz-Prigge, S;Moran, JV
通讯作者：
Moran, JV
影响因子：
64.8
作者：
通讯作者：
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