EpCAM Aptamer-mediated Survivin Silencing Sensitized Cancer Stem Cells to Doxorubicin in a Breast Cancer Model.
EpCAM Aptamer-mediated Survivin Silencing Sensitized Cancer Stem Cells to Doxorubicin in a Breast Cancer Model.
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作者：
Wang T;Gantier MP;Xiang D;Bean AG;Bruce M;Zhou SF;Khasraw M;Ward A;Wang L;Wei MQ;AlShamaileh H;Chen L;She X;Lin J;Kong L;Shigdar S;Duan W
了解耐药性的分子基础并利用这些信息来克服化疗耐药性仍然是肿瘤学中的一个关键挑战。在这里，我们报告了Survivin，一个与耐药性有关的关键蛋白，在阿霉素耐药的乳腺癌细胞的癌症干细胞库中过表达。此外，通过利用一个由靶向上皮细胞黏附分子的RNA适配子和底物Survivin siRNA组成的主动靶向系统，我们可以将高剂量的siRNA输送到异种移植瘤中的癌症干细胞。重要的是，在癌症干细胞群体中，通过这种适体-siRNA嵌合体沉默Survivin导致了化疗耐药性的逆转，因此与低剂量阿霉素联合治疗抑制了干细胞的干性，通过凋亡消除了癌症干细胞，抑制了肿瘤生长，延长了携带化疗耐药肿瘤的小鼠的生存时间。这种体内肿瘤干细胞靶向的策略在未来有效沉默抗死亡基因以及与化疗耐药和肿瘤复发有关的任何异常基因方面具有广泛的应用。
Understanding the molecular basis of drug resistance and utilising this information to overcome chemoresistance remains a key challenge in oncology. Here we report that survivin, a key protein implicated in drug resistance, is overexpressed in cancer stem cell pool of doxorubicin-resistant breast cancer cells. Moreover, by utilising an active targeting system consisting of an RNA aptamer targeted against the epithelial cell adhesion molecule and a Dicer substrate survivin siRNA, we could deliver a high dose of the siRNA to cancer stem cells in xenograft tumours. Importantly, silencing of survivin with this aptamer-siRNA chimera in cancer stem cell population led to the reversal of chemoresistance, such that combined treatment with low dose of doxorubicin inhibited stemness, eliminated cancer stem cells via apoptosis, suppressed tumour growth, and prolonged survival in mice bearing chemoresistant tumours. This strategy for in vivo cancer stem cell targeting has wide application for future effective silencing of anti-death genes and in fact any dysregulated genes involved in chemoresistance and tumour relapse.