Dicer1 functions as a haploinsufficient tumor suppressor
Dicer1 functions as a haploinsufficient tumor suppressor
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DOI：
10.1101/gad.1848209
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发表时间：
2009-12-01
影响因子：
10.5
通讯作者：
Jacks, Tyler
中科院分区：
文献类型：
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作者：
Kumar, Madhu S.;Pester, Ryan E.;Jacks, Tyler
虽然 microRNA (miRNA) 的整体下调是人类肿瘤的一个共同特征，但其遗传基础在很大程度上尚不清楚。为了探讨这个问题，我们分析了条件性 Dicer1 突变（Dicer1“floxed”或 Dicer1(fl)）对几种小鼠癌症模型的影响。在这里，我们展示了 Dicer1 作为单倍体不足的肿瘤抑制基因的功能。与对照组相比，在 Dicer1(fl/+) 动物的肿瘤中删除 Dicer1 的单个拷贝会导致存活率降低。这些肿瘤表现出 miRNA 加工受损，但未能丢失野生型 Dicer1 等位基因。此外，来自 Dicer1(fl/fl) 动物的肿瘤始终保留一个功能性 Dicer1 等位基因。与针对 Dicer1 表达完全丧失的选择一致，强制 Dicer1 缺失会抑制肿瘤发生。对人类癌症基因组拷贝数数据的分析揭示了 DICER1 的频繁缺失。然而，重要的是，尚未报道该基因发生纯合缺失，这表明 DICER1 在人类癌症中单倍体不足。这些发现表明 Dicer1 可能是一个重要的单倍体不足的肿瘤抑制基因，此外，控制 miRNA 生物发生的其他因子也可能以这种方式发挥作用。
While the global down-regulation of microRNAs ( miRNAs) is a common feature of human tumors, its genetic basis is largely undefined. To explore this question, we analyzed the consequences of conditional Dicer1 mutation (Dicer1 "floxed" or Dicer1(fl)) on several mouse models of cancer. Here we show Dicer1 functions as a haploinsufficient tumor suppressor gene. Deletion of a single copy of Dicer1 in tumors from Dicer1(fl/+) animals led to reduced survival compared with controls. These tumors exhibited impaired miRNA processing but failed to lose the wild-type Dicer1 allele. Moreover, tumors from Dicer1(fl/fl) animals always maintained one functional Dicer1 allele. Consistent with selection against full loss of Dicer1 expression, enforced Dicer1 deletion caused inhibition of tumorigenesis. Analysis of human cancer genome copy number data reveals frequent deletion of DICER1. Importantly, however, the gene has not been reported to undergo homozygous deletion, suggesting that DICER1 is haploinsufficient in human cancer. These findings suggest Dicer1 may be an important haploinsufficient tumor suppressor gene and, furthermore, that other factors controlling miRNA biogenesis may also function in this manner.