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Cancer Therapy: Preclinical

Zinc Finger Nucleases Targeting the Human Papillomavirus E7 Oncogene Induce E7 Disruption and a Transformed Phenotype in HPV16/18-Positive Cervical Cancer Cells

Wencheng Ding, Zheng Hu, Da Zhu, Xiaohui Jiang, Lan Yu, Xiaoli Wang, Changlin Zhang, Liming Wang, Teng Ji, Kezhen Li, Dan He, Xi Xia, Dan Liu, Jianfeng Zhou, Ding Ma and Hui Wang
Wencheng Ding
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Zheng Hu
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Da Zhu
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Xiaohui Jiang
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Lan Yu
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Xiaoli Wang
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Changlin Zhang
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Liming Wang
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Teng Ji
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Kezhen Li
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Dan He
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Xi Xia
Center for Reproductive Medicine, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China.
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Dan Liu
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Jianfeng Zhou
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Ding Ma
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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  • For correspondence: dma@tjh.tjmu.edu.cnhuit71@sohu.com
Hui Wang
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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  • For correspondence: dma@tjh.tjmu.edu.cnhuit71@sohu.com
DOI: 10.1158/1078-0432.CCR-14-0250
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Abstract

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. Clin Cancer Res; 1–9. ©2014 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received February 15, 2014.
  • Revision received September 24, 2014.
  • Accepted October 1, 2014.
  • ©2014 American Association for Cancer Research.
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Published OnlineFirst November 24, 2014
doi: 10.1158/1078-0432.CCR-14-0250

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Zinc Finger Nucleases Targeting the Human Papillomavirus E7 Oncogene Induce E7 Disruption and a Transformed Phenotype in HPV16/18-Positive Cervical Cancer Cells
Wencheng Ding, Zheng Hu, Da Zhu, Xiaohui Jiang, Lan Yu, Xiaoli Wang, Changlin Zhang, Liming Wang, Teng Ji, Kezhen Li, Dan He, Xi Xia, Dan Liu, Jianfeng Zhou, Ding Ma and Hui Wang
Clin Cancer Res November 24 2014 DOI: 10.1158/1078-0432.CCR-14-0250

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Zinc Finger Nucleases Targeting the Human Papillomavirus E7 Oncogene Induce E7 Disruption and a Transformed Phenotype in HPV16/18-Positive Cervical Cancer Cells
Wencheng Ding, Zheng Hu, Da Zhu, Xiaohui Jiang, Lan Yu, Xiaoli Wang, Changlin Zhang, Liming Wang, Teng Ji, Kezhen Li, Dan He, Xi Xia, Dan Liu, Jianfeng Zhou, Ding Ma and Hui Wang
Clin Cancer Res November 24 2014 DOI: 10.1158/1078-0432.CCR-14-0250
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Clinical Cancer Research
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