Laboratory for Molecular Cancer Biology, Center for the Biology of Disease, VIB, 3000 Leuven, Belgium.
Nat Cell Biol. 2012 Sep;14(9):958-65. doi: 10.1038/ncb2556. Epub 2012 Aug 5.
Synthetic lethality is a promising strategy for specific targeting of cancer cells that carry mutations that are absent in normal cells. This approach may help overcome the challenge associated with targeting dysfunctional tumour suppressors, such as p53 and Rb (refs 1, 2). Here we show that Dicer1 targeting prevents retinoblastoma formation in mice by synthetic lethality with combined inactivation of p53 and Rb. Although Dicer1 functions as a haploinsufficient tumour suppressor, its complete loss of function is selected against during tumorigenesis(3-5). We show that Dicer1 deficiency is tolerated in Rb-deficient retinal progenitor cells harbouring an intact p53 pathway, but not in the absence of p53. This synthetic lethality is mediated by the oncogenic miR-17-92 cluster because its deletion phenocopies Dicer1 loss in this context. miR-17-92 inactivation suppresses retinoblastoma formation in mice and co-silencing of miR-17/20a and p53 cooperatively decreases the viability of human retinoblastoma cells. These data provide an explanation for the selective pressure against loss of Dicer1 during tumorigenesis and a proof-of-concept that targeting miRNAs may potentially represent a general approach for synthetic lethal targeting of cancer cells that harbour specific cancer-inducing genotypes.
合成致死性是一种有前途的策略，可以针对携带正常细胞中不存在的突变的癌细胞进行特异性靶向。这种方法可能有助于克服靶向功能失调的肿瘤抑制因子（如 p53 和 Rb）相关的挑战[1,2]。在这里，我们表明 Dicer1 靶向通过与 p53 和 Rb 的联合失活导致合成致死，从而阻止了小鼠的视网膜母细胞瘤形成。尽管 Dicer1 作为杂合不足的肿瘤抑制因子发挥作用，但在肿瘤发生过程中，其完全丧失功能会被选择淘汰[3-5]。我们表明，Dicer1 缺失在具有完整 p53 途径的 Rb 缺失视网膜祖细胞中是可以耐受的，但在没有 p53 的情况下则不行。这种合成致死性是由致癌的 miR-17-92 簇介导的，因为在这种情况下，其缺失可以模拟 Dicer1 的缺失表型。miR-17-92 的失活抑制了小鼠的视网膜母细胞瘤形成，并且 miR-17/20a 和 p53 的共沉默协同降低了人视网膜母细胞瘤细胞的活力。这些数据为肿瘤发生过程中对 Dicer1 缺失的选择性压力提供了一个解释，并证明了靶向 miRNAs 可能代表针对携带特定致癌基因型的癌细胞进行合成致死性靶向的一种通用方法。
