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学科主题: 临床医学
题名:
Zinc Finger Nucleases Targeting the Human Papillomavirus E7 Oncogene Induce E7 Disruption and a Transformed Phenotype in HPV16/18-Positive Cervical Cancer Cells
作者: Ding, Wencheng1; Hu, Zheng1; Zhu, Da1; Jiang, Xiaohui1; Yu, Lan1; Wang, Xiaoli1; Zhang, Changlin1; Wang, Liming1; Ji, Teng1; Li, Kezhen1; He, Dan2; Xia, Xi3; Liu, Dan1; Zhou, Jianfeng4; Ma, Ding1; Wang, Hui1
刊名: CLINICAL CANCER RESEARCH
发表日期: 2014-12-15
DOI: 10.1158/1078-0432.CCR-14-0250
卷: 20, 期:24, 页:6495-6503
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Oncology
研究领域[WOS]: Oncology
关键词[WOS]: RNA-INTERFERENCE ; T-CELLS ; GENE ; E6 ; TYPE-16 ; GENERATION ; WORLDWIDE ; KNOCKOUT ; CASKI ; DNA
英文摘要:

Purpose: Cervical cancer is mainly caused by infections of high-risk human papillomavirus (HR-HPV). Persistent expression of HR-HPV oncogenes E6 and E7 is implicated in malignant transformation. The aim was to provide proof-of-concept data to support use of zinc finger nucleases (ZFN) targeting HPV E7 to treat HPV-related cervical cancer.

Experimental Design: We designed and constructed ZFNs that could specifically recognize and cleave HPV16/18 E7 DNA. We tested the cleavage efficiency of selected ZFN16-E7-S2 and ZFN18-E7-S2 by using single-strand annealing (SSA) assay. Cell viability and colony formation assays were used to estimate the inhibition of cell growth that received treatments of ZFNs. Gene disruption of HPV E7 and downstream genes were examined by Western blotting. Cell apoptosis assay was used to test the specificity and efficiency of induction of HPV type-specific apoptosis. We also introduced xenograft formation assays to estimate the potential of inhibition of HPV-related disease.

Results: We found ZFN16-E7-S2 and ZFN18-E7-S2 disrupted HPV E7 oncogenes in HPV16/18-positive cervical cancer cells. Both ZFNs effectively led to inhibition of type-specific cervical cancer cell growth, and specifically induced apoptosis of corresponding HPV16-and HPV18-positive cervical cancer cell lines. ZFN16-E7-S2 and ZFN18-E7-S2 also repressed xenograft formation in vivo.

Conclusion: ZFNs targeting HPV16/18 E7 could effectively induce disruption of E7 oncogenes and lead to type-specific and efficient growth inhibition and apoptosis of HPV-positive cells. ZFNs targeting HPV16/ 18 E7 oncogenes could be used as novel therapeutic agents for the treatment of HPV-related cervical cancer. (C) 2014 AACR.

语种: 英语
所属项目编号: 2015CB553903 ; 2009CB521800 ; 2013CB911304 ; 2009CB521806 ; 81372805 ; 81090414 ; 81402158 ; 81471508 ; 81101971 ; 81402159 ; 81301126 ; 81302266
项目资助者: National Development Program (973) for Key Basic Research of China ; National Natural Science Funding of China (NSFC
WOS记录号: WOS:000346418100029
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/51840
Appears in Collections:北京大学深圳医院_生殖医学科_期刊论文

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作者单位: 1.Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Obstet & Gynecol, Wuhan 430030, Hubei, Peoples R China
2.Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Neurol, Wuhan 430030, Hubei, Peoples R China
3.Peking Univ, Shenzhen Hosp, Ctr Reprod Med, Shenzhen, Guangdong, Peoples R China
4.Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Hematol, Wuhan 430030, Hubei, Peoples R China

Recommended Citation:
Ding, Wencheng,Hu, Zheng,Zhu, Da,et al. Zinc Finger Nucleases Targeting the Human Papillomavirus E7 Oncogene Induce E7 Disruption and a Transformed Phenotype in HPV16/18-Positive Cervical Cancer Cells[J]. CLINICAL CANCER RESEARCH,2014,20(24):6495-6503.
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