Nuclear localization signal-enhanced RNA interference of EZH2 and Oct4 in the eradication of head and neck squamous Cell carcinoma-derived cancer stem cells
Nuclear localization signal-enhanced RNA interference of EZH2 and Oct4 in the eradication of head and neck squamous Cell carcinoma-derived cancer stem cells
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DOI：
10.1016/j.biomaterials.2012.01.016
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发表时间：
2012-05-01
期刊：
影响因子：
14
通讯作者：
Chiou, Shih-Hwa
中科院分区：
文献类型：
--
作者：
Lo, Wen-Liang;Chien, Yueh;Chiou, Shih-Hwa
转移是头颈部鳞状细胞癌（HNSCC）高死亡率的主要原因，其中可能涉及HNSCC衍生的癌症干细胞（CSCs）。一些报道将非病毒基因传递与RNA干扰（RNAi）结合起来，以靶向癌细胞中的特定基因。然而，RNAi的递送效率有限，有待提高。此外，非病毒基因传递方法对hnscc来源的CSCs的治疗效果仍不确定。在本研究中，我们发现EZH2和Oct4在hnscc衍生的ALDH1+/CD44+ csc样细胞中上调。基于聚氨酯短分支PEI （PU-PEI）的双链DNA （dsDNA）编码小干扰RNA （siRNA）对抗EZH2和Oct4 (siEZH2/siOct4)，导致部分抗癌能力和轻微抑制csc样性质。通过将核定位信号（NLS）预偶联到表达sirna的dsDNA上，提高了核传递量，从而增强了抗癌效果。值得注意的是，nls预偶联的sizh2 /siOct4在ALDH1+/CD44+ csc样细胞中构建了显著抑制的上皮-间质转分化（EMT）和放射耐药，其中Wnt5A和CyclinD1可能分别参与其中。我们进一步证明了这种改进的方法能够减少肿瘤的生长和转移。我们的发现可能提供一种可行的非病毒基因传递方法来根除HNSCC来源的CSCs，并改善HNSCC的治疗。(C) 2012 Elsevier Ltd.版权所有。
Metastasis is the major cause of high mortality in head and neck squamous cell carcinoma (HNSCC), in which HNSCC-derived cancer stem cells (CSCs) may be involved. Several reports have coupled non-viral gene delivery with RNA interference (RNAi) to target specific genes in cancer cells. However, the delivery efficiency of RNAi is limited and remained to be improved. Moreover, the therapeutic effect of non-viral gene delivery approaches on HNSCC-derived CSCs is still uncertain. In this study, we found that EZH2 and Oct4 are upregulated in HNSCC-derived ALDH1+/CD44+ CSC-like cells. Polyurethane-short branch PEI (PU-PEI)-based administration of double-stranded DNA (dsDNA) encoding small interfering RNA (siRNA) against EZH2 and Oct4 (siEZH2/siOct4) led to partial anti-cancer capacity and mild suppression of CSC-like properties. By pre-conjugation of nuclear localization signal (NLS) to siRNA-expressing dsDNA, the anti-cancer efficacy was enhanced due to elevated nuclear delivery. Notably, the NLS-preconjugated siEZH2/siOct4 constructs remarkably repressed epithelial-rnesenchymal transdifferentiation (EMT) and radioresistance in ALDH1+/CD44+ CSC-like cells, in which Wnt5A and CyclinD1 may be involved respectively. We furthermore demonstrated that this improved method was capable of reducing tumor growth and metastasis in vivo. Our findings may provide a feasible non-viral gene delivery method to eradicate HNSCC-derived CSCs and improve HNSCC therapy. (C) 2012 Elsevier Ltd. All rights reserved.