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TALEN-mediated targeting of HPV oncogenes ameliorates HPV-related cervical malignancy
Zheng Hu, … , Ding Ma, Hui Wang
Zheng Hu, … , Ding Ma, Hui Wang
Published December 15, 2014
Citation Information: J Clin Invest. 2015;125(1):425-436. https://doi.org/10.1172/JCI78206.
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Research Article Oncology

TALEN-mediated targeting of HPV oncogenes ameliorates HPV-related cervical malignancy

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Abstract

Persistent HPV infection is recognized as the main etiologic factor for cervical cancer. HPV expresses the oncoproteins E6 and E7, both of which play key roles in maintaining viral infection and promoting carcinogenesis. While siRNA-mediated targeting of E6 and E7 transcripts temporarily induces apoptosis in HPV-positive cells, it does not eliminate viral DNA within the host genome, which can harbor escape mutants. Here, we demonstrated that specifically targeting E6 and E7 within host DNA with transcription activator–like effector nucleases (TALENs) induces apoptosis, inhibits growth, and reduces tumorigenicity in HPV-positive cell lines. TALEN treatment efficiently disrupted E6 and E7 oncogenes, leading to the restoration of host tumor suppressors p53 and retinoblastoma 1 (RB1), which are targeted by E6 and E7, respectively. In the K14-HPV16 transgenic mouse model of HPV-driven neoplasms, direct cervical application of HPV16-E7–targeted TALENs effectively mutated the E7 oncogene, reduced viral DNA load, and restored RB1 function and downstream targets transcription factor E2F1 and cycling-dependent kinase 2 (CDK2), thereby reversing the malignant phenotype. Together, the results from our study suggest that TALENs have potential as a therapeutic strategy for HPV infection and related cervical malignancy.

Authors

Zheng Hu, Wencheng Ding, Da Zhu, Lan Yu, Xiaohui Jiang, Xiaoli Wang, Changlin Zhang, Liming Wang, Teng Ji, Dan Liu, Dan He, Xi Xia, Tao Zhu, Juncheng Wei, Peng Wu, Changyu Wang, Ling Xi, Qinglei Gao, Gang Chen, Rong Liu, Kezhen Li, Shuang Li, Shixuan Wang, Jianfeng Zhou, Ding Ma, Hui Wang

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Figure 2

TALENs induce cell apoptosis and arrest growth subtype — specifically in vitro and in vivo.

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TALENs induce cell apoptosis and arrest growth subtype — specifically in...
(A and B) Apoptosis rate of HPV16-positive S12, HPV16-positive SiHa, HPV18-positive HeLa, HPV-negative C33A, and HPV-negative HEK293 cells 48 hours after treatment with (A) HPV16-E6-T27 and HPV16-E7-T512 and (B) HPV18-E6-T34 and HPV18-E7-T519. Error bars indicate the mean ± SD; *P < 0.01, compared to the untreated cells, 2-tailed Student’s t test; n = 3 per group. (C–G) Growth curves of TALEN-treated (C) SiHa, (D) S12, (E) HeLa, (F) C33A, and (G) HEK293 cells were constructed using the CCK-8 assay. All experiments were performed in triplicate. Data represent mean ± SD; *P < 0.01, compared to the untreated cells, 2-tailed Student’s t test; n = 3 per group. (H–K) Representative images of in vivo xenografts of SiHa and HeLa cells after treatment with TALENs for 30 days in nude mice and the calculated tumor sizes. (H) SiHa xenografts after treatment with T34 and T27. (I) SiHa xenografts after treatment with T519 and T512. (J) HeLa xenografts after treatment with T27 and T34. (K) HeLa xenografts after treatment with T512 and T519. The column scatter plots were used to present every data point, and the lines represent mean ± SD; *P < 0.05, **P < 0.01, 2-tailed Student’s t test; n = 4 per group.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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