Monoallelic but not biallelic loss of Dicer1 promotes tumorigenesis in vivo.
Monoallelic but not biallelic loss of Dicer1 promotes tumorigenesis in vivo.
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DOI：
10.1038/cdd.2009.202
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发表时间：
2010-04
影响因子：
12.4
通讯作者：
Marine, J-C
中科院分区：
文献类型：
--
作者：
Lambertz, I.;Nittner, D.;Mestdagh, P.;Denecker, G.;Vandesompele, J.;Dyer, M. A.;Marine, J-C
人类肿瘤的特征是微小RNA（miRNA）表达广泛降低，尽管尚不清楚这种变化是如何发生的，以及它们在疾病中是否具有病因学作用。重要的是，已表明miRNA敲低可增强人肺腺癌细胞的致瘤潜能。miRNA加工缺陷是全局下调的一种可能机制。为了在体内更详细地探究这种可能性，我们在视网膜母细胞瘤小鼠模型中操纵了Dicer1基因剂量。我们表明，虽然Dicer1的单等位基因缺失不影响正常视网膜发育，但在视网膜母细胞瘤敏感的背景下，它会显著加速肿瘤形成。重要的是，这些肿瘤保留了一个野生型Dicer1等位基因，并且在miRNA加工方面仅表现出部分降低。相应地，对人类癌症基因组数据的计算机分析显示，DICER1经常出现半合子缺失，但不是纯合子缺失。令人惊讶的是，小鼠中Dicer1功能完全丧失并没有加速视网膜母细胞瘤的形成。对这些肿瘤的miRNA分析确定let - 7和miR - 34家族成员为视网膜母细胞瘤中的候选肿瘤抑制因子。我们得出结论，Dicer1作为一种单倍体不足的肿瘤抑制因子发挥作用。这一发现对癌症病因学和癌症治疗具有重要意义。
Human tumors are characterized by widespread reduction in microRNA (miRNA) expression, although it is unclear how such changes come about and whether they have an etiological role in the disease. Importantly, miRNA-knockdown has been shown to enhance the tumorigenic potential of human lung adenocarcinoma cells. A defect in miRNA-processing is one possible mechanism for the global down-regulation. To explore this possibility in more detail in vivo we have manipulated Dicer1 gene dosage in a mouse model of retinoblastoma. We show that while monoallelic loss of Dicer1 does not affect normal retinal development it dramatically accelerates tumor formation on a retinoblastoma-sensitized background. Importantly, these tumors retain one wild-type Dicer1 allele and exhibit only partial decrease in miRNA-processing. Accordingly, in silico analysis of human cancer genome data reveals frequent hemizygous, but not homozygous, deletions of DICER1. Strikingly, complete loss of Dicer1 function in mice did not accelerate retinoblastoma formation. miRNA profiling of these tumors identified members of the let-7 and miR-34 families as candidate tumor suppressors in retinoblastoma. We conclude that Dicer1 functions as a haploinsufficient tumor suppressor. This finding has implications for cancer aetiology and cancer therapy.
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影响因子：
64.8
作者：
Lu, J;Getz, G;Golub, TR
通讯作者：
Golub, TR
影响因子：
64.8
作者：
Laurie, Nikia A.;Donovan, Stacy L.;Dyer, Michael A.
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Jochemsen, Aart G.
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Takahashi, T
影响因子：
5.3
作者：
Dyer, MA;Cepko, CL
通讯作者：
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