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Published in: Journal of Cancer Research and Clinical Oncology 1/2024

Open Access 01-01-2025 | Human Papillomavirus | Research

Human papillomavirus E7 protein induces homologous recombination defects and PARPi sensitivity

Authors: Siqi He, Ao Wang, Jing Wang, Zizhi Tang, Xiaojun Wang, Danqing Wang, Jie Chen, Cong Liu, Mingcai Zhao, Hui Chen, Liang Song

Published in: Journal of Cancer Research and Clinical Oncology | Issue 1/2024

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Abstract

Purpose

Cervical cancer is a common gynecological malignancy, pathologically associated with persistent infection of high-risk types of human papillomavirus (HPV). Previous studies revealed that HPV-positive cervical cancer displays genomic instability; however, the underlying mechanism is not fully understood.

Methods

To investigate if DNA damage responses are aggravated in precancerous lesions of HPV-positive cervical epithelium, cervical tissues were biopsied and cryosectioned, and subjected to immunofluorescent staining. Cloned HA-tagged E6 and E7 genes of HPV16 subtype were transfected into HEK293T or C33A cells, and indirect immunofluorescent staining was applied to reveal the competency of double strand break (DSB) repair. To test the synthetic lethality of E7-indued HRD and PARP inhibitor (PARPi), we expressed E7 in C33A cells in the presence or absence of olaparib, and evaluated cell viability by colony formation.

Results

In precancerous lesions, endogenous DNA lesions were elevated along with the severity of CIN grade. Expressing high-risk viral factor (E7) in HPV-negative cervical cells did not impair checkpoint activation upon genotoxic insults, but affected the potential of DSB repair, leading to homologous recombination deficiency (HRD). Based on this HPV-induced genomic instability, the viability of E7-expressing cells was reduced upon exposure to PARPi in comparison with control cells.

Conclusion

In aggregate, our findings demonstrate that HPV-E7 is a potential driver for genome instability and provides a new angle to understand its role in cancer development. The viral HRD could be employed to target HPV-positive cervical cancer via synthetic lethality.
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Metadata
Title
Human papillomavirus E7 protein induces homologous recombination defects and PARPi sensitivity
Authors
Siqi He
Ao Wang
Jing Wang
Zizhi Tang
Xiaojun Wang
Danqing Wang
Jie Chen
Cong Liu
Mingcai Zhao
Hui Chen
Liang Song
Publication date
01-01-2025
Publisher
Springer Berlin Heidelberg
Published in
Journal of Cancer Research and Clinical Oncology / Issue 1/2024
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-023-05511-6

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