Oncoproteins E6 and E7 upregulate topoisomerase I to activate the cGAS-PD-L1 pathway in cervical cancer development

作者全名："Luo, Ying; Niu, Mengda; Liu, Yanfei; Zhang, Miaochang; Deng, Yuanyuan; Mu, Dan; Xu, Junfen; Hong, Shiyuan"

作者地址："[Luo, Ying; Niu, Mengda; Liu, Yanfei; Zhang, Miaochang; Deng, Yuanyuan; Mu, Dan; Hong, Shiyuan] Chongqing Med Univ, Coll Pharm, Chongqing, Peoples R China; [Xu, Junfen] Zhejiang Univ, Sch Med, Womens Hosp, Dept Gynecol Oncol, Hangzhou, Zhejiang, Peoples R China"

通信作者："Hong, SY (通讯作者)，Chongqing Med Univ, Coll Pharm, Chongqing, Peoples R China.; Xu, JF (通讯作者)，Zhejiang Univ, Sch Med, Womens Hosp, Dept Gynecol Oncol, Hangzhou, Zhejiang, Peoples R China."

来源：FRONTIERS IN PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001291031800001

JCR分区：Q1

影响因子：5.6

年份：2024

卷号：15

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：DDR; TOP1; cGAS; PD-L1; human papillomavirus; cervical cancer

摘要："Background: Cervical cancer (CC) stands as a significant health threat to women globally, with high-risk human papillomaviruses as major etiologic agents. The DNA damage repair (DDR) protein topoisomerase I (TOP1) has been linked to various cancers, yet its distinct roles and mechanisms in CC are not fully elucidated.Methods: We investigated TOP1 expression in cervical intraepithelial neoplasia (CIN) and CC tissues utilizing qRT-PCR and IHC, correlating findings with patient prognosis. Subsequent knockdown studies were performed in vitro and in vivo to evaluate the influence of TOP1 on tumor growth, DNA repair, and inflammatory responses.Results: TOP1 was highly expressed in CIN and CC, negatively correlating with patient prognosis. Inhibition of TOP1 impeded CC cell growth and disrupted DNA repair. TOP1 was shown to regulate tumor-promoting inflammation and programmed death-ligand 1 (PD-L1) production in a cGAS-dependent manner. HPV oncoproteins E6 and E7 upregulated TOP1 and activated the cGAS-PD-L1 pathway.Conclusions: TOP1 acts as a DNA repair mediator, promoting CC development and immune evasion. Targeting the TOP1-cGAS-PD-L1 axis could be a potential therapeutic strategy for CC."

基金机构：Open Fund from Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases [ZDFY2022-CD-4]; National Natural Science Foundation of China [82072855]; CQMU Program for Youth Innovation in Future Medicine [172020320220090 W0072]; Chongqing Yuzhong District Basic Research and Frontier Exploration Project [20210128]; Swedish Heart-Lung Foundation [20210128] Funding Source: Swedish Heart-Lung Foundation

基金资助正文："The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was supported by Open Fund from Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases (ZDFY2022-CD-4), the National Natural Science Foundation of China (82072855), CQMU Program for Youth Innovation in Future Medicine (172020320220090 W0072), and Chongqing Yuzhong District Basic Research and Frontier Exploration Project (20210128)."