Luo Ying, Niu Mengda, Liu Yanfei, Zhang Miaochang, Deng Yuanyuan, Mu Dan, Xu Junfen, Hong Shiyuan
College of Pharmacy, Chongqing Medical University, Chongqing, China.
Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Front Pharmacol. 2024 Aug 2;15:1450875. doi: 10.3389/fphar.2024.1450875. eCollection 2024.
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. 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 and to evaluate the influence of TOP1 on tumor growth, DNA repair, and inflammatory responses. 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. 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.
宫颈癌（CC）是全球女性面临的重大健康威胁，高危型人乳头瘤病毒是主要病因。DNA损伤修复（DDR）蛋白拓扑异构酶I（TOP1）与多种癌症相关，但其在宫颈癌中的独特作用和机制尚未完全阐明。我们利用qRT-PCR和免疫组化（IHC）研究了拓扑异构酶I（TOP1）在宫颈上皮内瘤变（CIN）和宫颈癌组织中的表达，并将结果与患者预后相关联。随后进行了敲低研究，以评估TOP1对肿瘤生长、DNA修复和炎症反应的影响。TOP1在CIN和宫颈癌中高表达，与患者预后呈负相关。抑制TOP1可阻碍宫颈癌细胞生长并破坏DNA修复。研究表明，TOP1以一种依赖于环鸟苷酸合成酶（cGAS）的方式调节促肿瘤炎症和程序性死亡配体1（PD-L1）的产生。人乳头瘤病毒（HPV）癌蛋白E6和E7上调TOP1并激活cGAS-PD-L1通路。TOP1作为DNA修复介质，促进宫颈癌的发展和免疫逃逸。靶向TOP1-cGAS-PD-L1轴可能是宫颈癌的一种潜在治疗策略。
