siRNA targeting of the viral E6 oncogene efficiently kills human papillomavirus-positive cancer cells
siRNA targeting of the viral E6 oncogene efficiently kills human papillomavirus-positive cancer cells
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DOI：
10.1038/sj.onc.1206894
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发表时间：
2003-09-04
期刊：
影响因子：
8
通讯作者：
Hoppe-Seyler, F
中科院分区：
文献类型：
--
作者：
Butz, K;Ristriani, T;Hoppe-Seyler, F
靶向抑制肿瘤细胞中的抗凋亡因子可能为开发新的抗癌疗法提供一种合理的方法。以人乳头瘤病毒（HPV）转化的细胞为模型系统，研究了RNA干扰（RNAi）介导的基因沉默能否克服癌细胞的凋亡抗性。我们发现，载体携带的和合成的小干扰（si）RNA，专门针对抗凋亡HPV E6癌基因，恢复了HPV阳性癌细胞中的休眠肿瘤抑制通路，否则在E6的存在下是不活跃的。这最终导致大规模的细胞凋亡，选择性地在HPV阳性肿瘤细胞中。这些发现表明，RNAi提供了一个强大的分子策略，有效地抑制细胞内E6的功能。此外，他们将E6定义为通过RNAi特异性消除HPV阳性肿瘤细胞的最有前途的治疗靶点。因此，通过序列特异性靶向抗凋亡基因，siRNA可以开发成新的治疗剂，可以有效地纠正癌细胞的凋亡缺陷。
The targeted inhibition of antiapoptotic factors in tumour cells may provide a rational approach towards the development of novel anticancer therapies. Using human papillomavirus (HPV)-transformed cells as a model system, we investigated if RNA interference (RNAi)-mediated gene silencing can be employed in order to overcome the apoptosis resistance of cancer cells. We found that both vector-borne and synthetic small interfering (si)RNAs, specifically directed against the antiapoptotic HPV E6 oncogene, restored dormant tumour suppressor pathways in HPV-positive cancer cells that are otherwise inactive in the presence of E6. This ultimately resulted in massive apoptotic cell death, selectively in HPV-positive tumour cells. These findings show that RNAi provides a powerful molecular strategy to inactivate intracellular E6 function efficiently. Moreover, they define E6 as a most promising therapeutic target to eliminate HPV-positive tumour cells specifically by RNAi. Thus, by sequence-specific targeting of antiapoptotic genes, siRNAs may be developed into novel therapeutics that can efficiently correct the apoptosis deficiency of cancer cells.