Slug (SNAI2) down-regulation by RNA interference facilitates apoptosis and inhibits invasive growth in neuroblastoma preclinical models.
Slug (SNAI2) down-regulation by RNA interference facilitates apoptosis and inhibits invasive growth in neuroblastoma preclinical models.
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DOI：
10.1158/1078-0432.ccr-07-5210
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发表时间：
2008-07-15
期刊：
影响因子：
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通讯作者：
Raschellà G
中科院分区：
文献类型：
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作者：
Vitali R;Mancini C;Cesi V;Tanno B;Mancuso M;Bossi G;Zhang Y;Martinez RV;Calabretta B;Dominici C;Raschellà G
我们评估了Slug（SNAI2）与神经母细胞瘤（NB）细胞体外和体内抗凋亡和侵袭潜力的相关性。我们评估了甲磺酸伊马替尼（IM）对NB细胞侵袭的影响，并分析了IM治疗调节的基因。通过RNA干扰在NB细胞中敲低IM处理抑制的Slug表达，并在体外评估对侵袭和凋亡的影响。使用SCID小鼠中NB的假转移模型来评估Slug沉默单独或与IM治疗组合对转移发展的影响。微阵列分析显示，包括Slug在内的几个基因被IM下调。在10个人NB细胞系中的8个中可检测到Slug表达。用编码针对Slug mRNA的miRNA的载体感染两种Slug表达细胞系。检测了Slug水平降低的感染细胞中先前被鉴定为Slug靶标的前列腺增生相关基因（p53、Bax、Bcl-2）的表达。Bcl-2在Slug干预的细胞中下调。Slug下调增加了对IM、依托泊苷或多柔比星诱导的细胞凋亡的敏感性。Slug沉默细胞的体外侵袭减少。注射Slug沉默细胞的动物比对照组具有更少的肿瘤，并且在用IM治疗的动物中肿瘤生长的抑制甚至更高。Slug下调促进促凋亡药物在NB细胞中诱导的凋亡，并降低其在体外和体内的侵袭能力。Slug抑制，可能与IM结合，可能代表治疗转移性NB的新策略。
We assessed the relevance of Slug (SNAI2) for apoptosis resistance and invasion potential of neuroblastoma (NB) cells in vitro and in vivo. We evaluated the effect of Imatinib Mesylate (IM) on invasion and analyzed the genes modulated by IM treatment in NB cells. Slug expression, inhibited by IM treatment, was knocked-down in NB cells by RNA interference and the effects on invasion and apoptosis were evaluated in vitro. A pseudometastatic model of NB in SCID mice was used to assess the effects of Slug-silencing alone or in combination with IM treatment on metastasis development. Microarray analysis revealed that several genes, including Slug, were down-regulated by IM. Slug expression was detectable in 8 of 10 human NB cell lines. Two Slug-expressing cell lines were infected with a vector encoding a miRNA to Slug mRNA. Infected cells with reduced levels of Slug were tested for the expression of apoptosis-related genes (p53, Bax, Bcl-2), previously identified as Slug targets. Bcl-2 was down-regulated in Slug-interfered cells. Slug down-regulation increased sensitivity to apoptosis induced by IM, etoposide or doxorubicin. Invasion of Slug-silenced cells was reduced in vitro. Animals injected with Slug-silenced cells had fewer tumors than controls and the inhibition of tumor growth was even higher in animals treated with IM. Slug down-regulation facilitates apoptosis induced by pro-apoptotic drugs in NB cells and decreases their invasion capability in vitro and in vivo. Slug inhibition, possibly combined with IM, may represent a novel strategy for treatment of metastatic NB.