Topoisomerase IIα orchestrates secretion of IL-6 and IL-8 with human papillomavirus replication

Yanfei Liu; Zi Han; Paul Kaminski; Chengcheng Tao; Xiaoge Li; Mengmeng Liu; Yang Li; Ying Jia; Junfen Xu; Shiyuan Hong

doi:10.1016/j.virs.2025.11.004

December 2025

Citation: Yanfei Liu, Zi Han, Paul Kaminski, Chengcheng Tao, Xiaoge Li, Mengmeng Liu, Yang Li, Ying Jia, Junfen Xu, Shiyuan Hong. Topoisomerase IIα orchestrates secretion of IL-6 and IL-8 with human papillomavirus replication .VIROLOGICA SINICA, 2025, 40(6) : 946-961. http://dx.doi.org/10.1016/j.virs.2025.11.004

Topoisomerase IIα orchestrates secretion of IL-6 and IL-8 with human papillomavirus replication

Yanfei Liu ^a ,
Zi Han ^a ,
Paul Kaminski ^e ,
Chengcheng Tao ^a ,
Xiaoge Li ^b ,
Mengmeng Liu ^c ,
Yang Li ^a ,
Ying Jia ^b ,
Junfen Xu ^{d
,,} ,
Shiyuan Hong ^{a
,,}

a. College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China;
b. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China;
c. Office of Research Administration, Chongqing Medical University, Chongqing, 400016, China;
d. Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China;
e. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, United States of America

Corresponding author: Junfen Xu, xjfzu@zju.edu.cn
Shiyuan Hong, hongshiyuan@cqmu.edu.cn
Received Date: 29 July 2025
Accepted Date: 11 November 2025
Available online: 19 November 2025

Abstract

High-risk human papillomavirus (HPV) replication requires deregulation of host DNA damage response (DDR) and inflammatory pathways. DNA topoisomerase 2β (Top2β) was previously shown to promote HPV replication. We investigated whether its paralog Top2α protein acts similarly to the virus. Elevated levels of Top2α are consistently observed in cervical intraepithelial lesions and the related carcinomas, as well as in HPV-positive cell lines. Silencing Top2α with shRNA severely suppresses HPV genome maintenance and amplification, but in a DDR-independent manner. Instead, Top2α facilitates secretion of interleukin (IL)-6 and IL-8, which are necessary for HPV replication. Mechanistically, this manipulation is regulated by toll-like receptor 4 (TLR4). Top2α binds to the TLR4 promoter to transcriptionally induce TLR4 expression. Blockade of TLR4 signaling by the specific inhibitor TAK-242 significantly reduces the secreted IL-6/IL-8 levels and HPV replication. Overall, our results reveal a novel role of Top2α to shape the inflammatory microenvironment that benefits HPV replication, making it a promising therapeutic target for HPV-associated diseases.
- Human papillomavirus (HPV)
- , Replication
- , Topoisomerase 2α
- , IL-6/IL-8 secretion
- , TLR4

Electronic Supplementary Material

10.1016j.virs.2025.11.004-ESM1.docx
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