title: TALEN-mediated targeting of HPV oncogenes ameliorates HPV-related cervical malignancy.
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.forename: Zheng
authors.initials: Z
authors.lastname: Hu
authors.forename: Wencheng
authors.initials: W
authors.lastname: Ding
authors.forename: Da
authors.initials: D
authors.lastname: Zhu
authors.forename: Lan
authors.initials: L
authors.lastname: Yu
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Jiang
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.forename: Changlin
authors.initials: C
authors.lastname: Zhang
authors.forename: Liming
authors.initials: L
authors.lastname: Wang
authors.forename: Teng
authors.initials: T
authors.lastname: Ji
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Dan
authors.initials: D
authors.lastname: He
authors.forename: Xi
authors.initials: X
authors.lastname: Xia
authors.forename: Tao
authors.initials: T
authors.lastname: Zhu
authors.forename: Juncheng
authors.initials: J
authors.lastname: Wei
authors.forename: Peng
authors.initials: P
authors.lastname: Wu
authors.forename: Changyu
authors.initials: C
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Xi
authors.forename: Qinglei
authors.initials: Q
authors.lastname: Gao
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.forename: Kezhen
authors.initials: K
authors.lastname: Li
authors.forename: Shuang
authors.initials: S
authors.lastname: Li
authors.forename: Shixuan
authors.initials: S
authors.lastname: Wang
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhou
authors.forename: Ding
authors.initials: D
authors.lastname: Ma
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D053837:DNA Cleavage; D004279:DNA, Viral / Q000235:genetics; D003851:Deoxyribonucleases / Q000627:therapeutic use*; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D052162:Human papillomavirus 16 / Q000235:genetics; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D050725:Papillomavirus E7 Proteins / Q000235:genetics*; D030361:Papillomavirus Infections / Q000628:therapy* / Q000821:virology; D012097:Repressor Proteins / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000628:therapy* / Q000821:virology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004279:DNA, Viral; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D003851:Deoxyribonucleases