Induction of cell death in human papillomavirus 18-positive cervical cancer cells by E6 siRNA
Induction of cell death in human papillomavirus 18-positive cervical cancer cells by E6 siRNA
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DOI：
10.1038/sj.cgt.7700891
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发表时间：
2006-03-01
影响因子：
6.4
通讯作者：
Yoshinouchi, M
中科院分区：
文献类型：
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作者：
Yamato, K;Fen, J;Yoshinouchi, M
人宫颈癌是由高危型人乳头瘤病毒（HPV）如HPV 16和HPV 18引起的，其具有E6和E7癌基因，其同时表达是癌症发展和维持恶性表型的先决条件。沉默这些癌基因被认为适用于人宫颈癌的分子治疗。然而，它仍然有待确定是否E6，E7，或两者都应该沉默，以获得最有效的抗肿瘤活性的HPV小干扰RNA（siRNA）。在此，我们报告了两种类型的siRNA靶向HPV 18 E6，其对HPV 18阳性宫颈癌细胞（HeLa和SW 756）产生负生长效应，部分诱导细胞死亡。设计为靶向E6-E7 mRNA及其剪接变体E6*I-E7 mRNA的一种siRNA（Ex-18 E6）有效地敲低E6和E7表达。另一种（Sp-18 E6）被设计为特异性靶向E6-E7 mRNA，但不靶向E6*I-E7 mRNA，将E6抑制至与Ex-18 E6相似的水平;然而，与Ex-18 E6相比，其抑制E7的效率较低。尽管两种siRNA均诱导细胞死亡，但Sp-18 E6 siRNA比Ex-18 E6诱导更显著的细胞死亡。我们的研究结果表明，E6特异性抑制可能比同时抑制E6和E7诱导更有效的抗癌活性，并且E6特异性靶向是HPV阳性宫颈癌基于siRNA的治疗的一种有前途的策略。
Human cervical cancer is caused by high-risk types of human papillomavirus (HPV) such as HPV16 and HPV18, which possess the E6 and E7 oncogenes, whose concurrent expression is a prerequisite for cancer development and maintaining malignant phenotypes. Silencing these oncogenes is considered to be applicable in molecular therapies of human cervical cancer. However, it remains to be determined whether E6, E7, or both should be silenced to obtain most efficient antitumor activity by an HPV small-interfering RNA (siRNA). Herein, we report two types of siRNAs targeting HPV18 E6, that exerted a negative growth effect on HPV18-positive cervical cancer cells (HeLa and SW756), in part, inducing cell death. One siRNA (Ex-18E6), designed to target both E6-E7 mRNA and its splicing variant, E6*I-E7 mRNA, efficiently knocked down both E6 and E7 expression. The other (Sp-18E6), designed to specifically target E6-E7 mRNA but not E6*I-E7 mRNA, suppressed E6 to a similar level as Ex-18E6; however, it less efficiently inhibited E7 as compared to Ex-18E6. Although both siRNAs induced cell death, Sp-18E6 siRNA induced more prominent cell death than Ex-18E6. Our results suggest that E6-specific suppression may induce more potent anticancer activity than simultaneous E6 and E7 suppression, and that E6-specific targeting is a promising strategy for siRNA-based therapy for HPV-positive cervical cancer.