AUTHOR=Luo Ying , Niu Mengda , Liu Yanfei , Zhang Miaochang , Deng Yuanyuan , Mu Dan , Xu Junfen , Hong Shiyuan 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1450875

DOI=10.3389/fphar.2024.1450875

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Methods:</bold> 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 <italic>in vitro</italic> and <italic>in vivo</italic> to evaluate the influence of TOP1 on tumor growth, DNA repair, and inflammatory responses.</p><p><bold>Results:</bold> 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.</p><p><bold>Conclusions:</bold> 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.</p>