Activation of STING inhibits cervical cancer tumor growth through enhancing the anti-tumor immune response
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Activation of STING inhibits cervical cancer tumor growth through enhancing the anti-tumor immune response Fan Shi1 · Jin Su1 · Juan Wang1 · Zi Liu1 · Tao Wang1 Received: 15 July 2020 / Accepted: 27 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Cervical cancer remains the second leading cause of gynecologic cancer-related mortality among women worldwide. STING (stimulator of interferon genes) was reported to be involved in the immune surveillance of tumors. However, the specific role of STING in cervical cancer remains unclear. In this study, we found that the cGAS (Cyclic GMP-AMP synthase)/STING signal decreased in cervical cancer cells. Knockdown of STING by siRNA enhanced the cell viability and migration of cervical cancer cells, while activation of STING by ADU-S100 inhibited the cell viability of cervical cancer cells, with no effect on the migration and apoptosis. In addition, ADU-S100 promoted the secretion of IFNβ and IL-6, and the activation of TBK1 (TANK-binding kinase 1)/NF-κB (nuclear factor kappa-B) pathway. Meanwhile, knockdown of STING inhibited the production of IFNβ and IL-6 that were triggered by dsDNA and suppressed the TBK1/NF-κB signaling. ADU-S100 also suppressed tumor growth in vivo and increased the tumor-infiltrating CD8+ T cell and CD103+ dendritic cell numbers. The NF-κB signal inhibitor limited the increasing numbers of C D8+ T cell and C D103+ dendritic cells induced by ADU-S100, without influence on tumor growth. Hence, our study suggested that STING could serve as a potential novel immunotherapeutic target for cervical cancer. Keywords STING · TBK1/NF-κB · Cervical cancer · IFNβ · Immune response
Introduction Cervical cancer is a global health crisis to women. There are 528,000 new cervical cancer cases and about 266,000 deaths each year worldwide [1]. Approximately, 95% of cervical cancer cases are induced by persistent infections with highrisk human papillomavirus (HPV) [2]. Although prophylactic vaccines against carcinogenic HPV types are available, they had limited success [3]; women with already persistent HPV will develop cervical cancer later in their lives. On the other hand, local invasion and distant lymphatic metastasis lead to a poor prognosis in cervical cancer patients [4]. Therefore, it is necessary to provide new insight into the prevention and therapeutic management of cervical cancer. Stimulator of interferon genes (STING) is a transmembrane protein that serves as an important adaptor for * Tao Wang [email protected] 1
Department of Radiation Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, No.277 West yanta road, Xi’an 710061, China
cytosolic DNA sensing pathway [5]. Cyclic GMP-AMP synthase (cGAS) is an enzyme that can sense intracellular pathogens and mediate the downstream inflammatory reaction [6]. cGAS binds with the cytoplasmic DNA, leading to the generation of cyclic GMP-AMP (cGAMP), which binds and activates the STING and triggers the production of immune mediators and inflamm
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