Nuclear localization signal-enhanced RNA interference of EZH2 and Oct4 in the eradication of head and neck squamous Cell carcinoma-derived cancer stem cells

Wen Liang Lo, Yueh Chien, Guang-Yuh Chiou, Ling Ming Tseng, Han Shui Hsu, Yuh Lih Chang, Kai Hsi Lu, Chian Shiu Chien, Mong Lien Wang, Yi Wei Chen, Pin I. Huang, Fang Wei Hu, Cheng Chia Yu, Pen Yuan Chu, Shih Hwa Chiou*

*Corresponding author for this work

研究成果: Article同行評審

30 引文 斯高帕斯(Scopus)

摘要

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-mesenchymal 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.

原文English
頁(從 - 到)3693-3709
頁數17
期刊Biomaterials
33
發行號14
DOIs
出版狀態Published - 1 五月 2012

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