5′-triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma
5′-triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma
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DOI：
10.1038/nm.1887
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发表时间：
2008-11-01
期刊：
影响因子：
82.9
通讯作者：
Hartmann, Gunther
中科院分区：
文献类型：
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作者：
Poeck, Hendrik;Besch, Robert;Hartmann, Gunther
遗传和表观遗传可塑性使肿瘤能够逃避单一靶向治疗。在这里，我们指导Bcl 2特异性短干扰RNA（siRNA）与5 '-三磷酸末端（3 p-siRNA）对黑色素瘤。胞浆抗病毒解旋酶视黄酸诱导的蛋白I（Rig-I，由Ddx 58编码）识别5 '-三磷酸，激活先天免疫细胞（例如树突状细胞），并直接诱导干扰素（IFN）的表达和肿瘤细胞的细胞凋亡。这些Rig-I介导的活性与siRNA介导的Bcl 2沉默协同作用，在体内肺转移中引起肿瘤细胞的大量凋亡。治疗活性需要自然杀伤细胞和IFN，以及Bcl-2的沉默，如通过用突变的Bcl-2靶进行拯救、通过肺转移中Bcl-2信使RNA的位点特异性切割和体内肿瘤细胞中Bcl-2蛋白的下调所证明的。总之，3 p-siRNA代表了一种基于单分子的方法，其中免疫细胞和肿瘤细胞水平上的Rig-I活化纠正了免疫无知，并且其中基因沉默纠正了控制肿瘤细胞存活的关键分子事件。
Genetic and epigenetic plasticity allows tumors to evade single-targeted treatments. Here we direct Bcl2-specific short interfering RNA ( siRNA) with 5'-triphosphate ends (3p-siRNA) against melanoma. Recognition of 5'-triphosphate by the cytosolic antiviral helicase retinoic acid - induced protein I ( Rig-I, encoded by Ddx58) activated innate immune cells such as dendritic cells and directly induced expression of interferons (IFNs) and apoptosis in tumor cells. These Rig-I- mediated activities synergized with siRNA-mediated Bcl2 silencing to provoke massive apoptosis of tumor cells in lung metastases in vivo. The therapeutic activity required natural killer cells and IFN, as well as silencing of Bcl2, as evidenced by rescue with a mutated Bcl2 target, by site-specific cleavage of Bcl2 messenger RNA in lung metastases and downregulation of Bcl-2 protein in tumor cells in vivo. Together, 3p-siRNA represents a single molecule - based approach in which Rig-I activation on both the immune- and tumor cell level corrects immune ignorance and in which gene silencing corrects key molecular events that govern tumor cell survival.