DNA damage repair factor TOP1 induces tumor-promoting inflammation and PD-L1 production via a cGAS-dependent manner during cervical cancer development

Abstract Cervical carcinogenesis is regulated by DNA damage repair (DDR) and inflammation. The DDR protein topoisomerase I (TOP1) has been implicated in various cancers due to its role in regulating genome stability. Recent studies have revealed that TOP1 regulates the anti-inflammatory response and TOP1 inhibition protects cells from COVID-19-induced death. However, the specific functions and mechanisms of TOP1 in cervical cancer (CC) remain unclear. Here, our research highlights the crucial role of TOP1 in the regulation of cervical tumorigenesis. TOP1 is highly expressed in cervical intraepithelial neoplasia (CIN) and CC tissues, which is negatively correlated with the prognosis of CC patients. Inhibiting TOP1 suppresses CC cell growth and impairs DNA repair both in vitro and in vivo. To trigger CC development, TOP1 promotes tumor-promoting inflammation and increases production of programmed death-ligand 1 (PD-L1) in cyclic GMP-AMP synthase (cGAS)-dependent manner. Human papillomavirus (HPV) oncoproteins E6 and E7 significantly upregulate TOP1 and facilitate activation of the cGAS-PD-L1 pathway. Our research demonstrates that TOP1 serves as a DNA repair factor, induces expression of tumor-promoting inflammatory genes and activates the non-canonical cGAS-PD-L1 pathway to promote CC development. Therefore, targeting TOP1-mediated cGAS-PD-L1 pathway could be a promising therapeutic strategy for CC.