title: Activated STING enhances Tregs infiltration in the HPV-related carcinogenesis of tongue squamous cells via the c-jun/CCL22 signal.
abstract: The negative role of the activated stimulator of IFN genes (STING) has been uncovered in autoinflammatory disease and cancer. However, the role of STING in virus-related carcinogenesis is not well known. Herein, HPV(+) tongue squamous cell carcinoma (TSCC) (n=25) and HPV(-) TSCC samples (n=25) were randomly collected and were verified by in situ hybridization (ISH) and p16 immunohistochemistry (IHC) to assess the expression and activated status of STING through IHC. The results showed that the expression of STING was up-regulated during the development of TSCC. Interestingly, although the expression of STING showed no difference between HPV(+/-) TSCC samples, the activated status of STING with dark staining around the nucleus was observed in HPV(+) TSCC samples. The role of activated STING was analyzed in three cell lines by siRNA and indicated that activated STING had no impact on cell viability or apoptosis but promoted the induction of several immunosuppressive cytokines, e.g., IL-10, IDO and CCL22, which facilitated the infiltration of regulatory T cells (Tregs). Moreover, increased infiltration of Foxp3(+) Tregs along with increased expression of CCL22 was confirmed in HPV(+) TSCC samples. An inhibitor of the MAPK/AP-1 pathway (U0126) and the silencing of c-jun significantly suppressed CCL22 induction and the recruitment of Tregs by activated STING. Furthermore, down-regulated miR-27 was verified in independent fresh TSCC samples (n=50) and eight cell lines, which enhanced STING activation and led to increased CCL22 expression for Tregs recruitment in the TSCC microenvironment. Therefore, our findings provided distinct insight into the side effects of activated STING in HPV-related carcinogenesis.
authors: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China.
authors: Ding
authors: D
authors: Liang
authors: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China.
authors: Huang
authors: H
authors: Xiao-Feng
authors: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China.
authors: Dong
authors: D
authors: Guan-Jun
authors: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China.
authors: Hu
authors: H
authors: Er-Ling
authors: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China.
authors: Chen
authors: C
authors: Sheng
authors: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China.
authors: Wang
authors: W
authors: Ting-Ting
authors: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China.
authors: Hu
authors: H
authors: Qin-Gang
authors: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China. Electronic address: niyanhong12@163.com.
authors: Ni
authors: N
authors: Yan-Hong
authors: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology and Hospital of Stomatology, Medical School, Nanjing University, Nanjing, China; Jiang su Key Laboratory of Molecular Medicine, Nanjing 210093, China. Electronic address: yayihou@nju.edu.cn.
authors: Hou
authors: H
authors: Ya-Yi
keywords: HPV; STING; Tregs; c-jun; miR-27